WO2015152117A1 - Alkynyl indazole derivative and use thereof - Google Patents
Alkynyl indazole derivative and use thereof Download PDFInfo
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- WO2015152117A1 WO2015152117A1 PCT/JP2015/059846 JP2015059846W WO2015152117A1 WO 2015152117 A1 WO2015152117 A1 WO 2015152117A1 JP 2015059846 W JP2015059846 W JP 2015059846W WO 2015152117 A1 WO2015152117 A1 WO 2015152117A1
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- 0 CCCC(CCC*C[C@]1C[C@](CCCC2CCCC2)CC1)*C Chemical compound CCCC(CCC*C[C@]1C[C@](CCCC2CCCC2)CC1)*C 0.000 description 3
- DAYOOBAZOAPZHD-UHFFFAOYSA-N CNC(c1ccccc1Sc(cc1)cc2c1c(C#Cc1cc(NC(NCCOC)=O)ccc1)n[nH]2)=O Chemical compound CNC(c1ccccc1Sc(cc1)cc2c1c(C#Cc1cc(NC(NCCOC)=O)ccc1)n[nH]2)=O DAYOOBAZOAPZHD-UHFFFAOYSA-N 0.000 description 1
- PCHCAAZSSXPKFA-UHFFFAOYSA-N COCCOCCOCCOCCNC(NC(NC=C1)=CC=C1C#C)=O Chemical compound COCCOCCOCCOCCNC(NC(NC=C1)=CC=C1C#C)=O PCHCAAZSSXPKFA-UHFFFAOYSA-N 0.000 description 1
- DSFZYLCRXIWFFW-UHFFFAOYSA-N O=C(c1ccccc1SSc(cccc1)c1C(Cl)=O)Cl Chemical compound O=C(c1ccccc1SSc(cccc1)c1C(Cl)=O)Cl DSFZYLCRXIWFFW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to an alkynylindazole derivative having a vascular endothelial growth factor receptor tyrosine kinase inhibitory action, a pharmaceutically acceptable salt thereof, and uses thereof.
- Angiogenesis in cells and tissues plays an important role in the process of development, wound healing, etc., but pathological angiogenesis is related to retinal diseases such as age-related macular degeneration and diabetic retinopathy, tumors It is known to be involved in various diseases or conditions such as the formation, proliferation or metastasis, chronic inflammation, rheumatoid arthritis, etc.
- VEGF receptors such as vascular endothelial growth factor (also referred to as vascular endothelial cell growth factor; hereinafter referred to as “VEGF”) receptor 2 are known as receptors involved in angiogenesis.
- the VEGF receptor is a type of receptor tyrosine kinase. When the ligand VEGF binds to the VEGF receptor, the receptor tyrosine kinase is activated and a signal is transmitted into the cell. As a result, for example, enhancement of vascular permeability, proliferation and migration of vascular endothelial cells are promoted, and angiogenesis is induced.
- VEGF receptor 2 is involved not only in normal body angiogenesis but also in pathological angiogenesis caused by the above-mentioned diseases or symptoms. Therefore, for example, by inhibiting the VEGF receptor 2 tyrosine kinase activity, it is possible to suppress angiogenesis caused by the kinase, and it is effective in the treatment of the diseases or symptoms associated with angiogenesis. . For this reason, various VEGF receptor 2 tyrosine kinase inhibitors have been developed for the purpose of preventing or treating diseases or symptoms associated with angiogenesis.
- Patent Document 1 discloses an indazole compound that inhibits the protein kinase activity of the VEGF receptor.
- Example 33 (a) of Patent Document 1 the following formula:
- Patent Document 2 discloses a method for preparing an indazole compound useful as a modulator and / or inhibitor of a protein kinase, and an intermediate thereof. For example, in Example 20, the following formula:
- Patent Document 3 discloses an indazole compound that modulates or inhibits the activity of VEGF receptor 2.
- Non-Patent Document 1 discloses an anticancer agent (for example, pazopanib, axitinib, sorafenib, sunitinib) containing a VEGF receptor kinase inhibitor.
- VEGF inhibitors Lucentis (registered trademark), McGen (registered trademark), and Airia (registered trademark) are used as medicaments for the treatment of age-related macular degeneration, which is a posterior ocular disease.
- These medicines contain a high molecular compound (an antibody against VEGF or an aptamer) that specifically binds to VEGF, but need to be administered intravitreally. Therefore, for example, in the field of ophthalmology, development of an angiogenesis inhibitor that can be administered more non-invasively is desired. However, an angiogenesis inhibitor that can be administered by eye drops has not yet been marketed.
- the main object of the present invention is to provide a novel compound having VEGF receptor tyrosine kinase inhibitory activity and useful as a therapeutic agent for diseases associated with angiogenesis or edema such as age-related macular degeneration.
- Another object of the present invention is to provide a compound having VEGF receptor tyrosine kinase inhibitory activity, high solubility in an aqueous solution, and excellent stability.
- an alkynylindazole derivative represented by the following general formula (I) and a salt thereof have excellent VEGF receptor tyrosine kinase inhibitory activity.
- the present invention has been reached.
- the alkynylindazole derivative represented by the following general formula (I) and a salt thereof have high solubility in an aqueous solution and are excellent in light stability in the solution.
- Axitinib marketed as an oral antineoplastic agent is an excellent VEGF receptor inhibitor having VEGF receptor tyrosine kinase inhibitory activity.
- axitinib When the present inventors tested whether axitinib can be applied to a liquid preparation such as eye drops, it was predicted that the solubility in an aqueous solution was low and the transferability to the posterior segment was not sufficient. It was also found that axinitib has poor photostability in aqueous solution. From these viewpoints, it has been difficult to apply axitinib to liquid preparations such as eye drops.
- the alkynylindazole derivative represented by the following general formula (I) and a salt thereof have a VEGF receptor tyrosine kinase inhibitory activity as described above, and have improved solubility in an aqueous solution. Since it is excellent in stability, it can be suitably used for liquid preparations such as eye drops.
- Examples of the present invention include the following alkynylindazole derivatives or pharmaceutically acceptable salts thereof, and pharmaceuticals containing the same.
- R 1 represents lower alkyl, and X and Y are the same or different and represent CH or N, provided that X and Y are not both N, and Z represents the following general formula (a):
- R 2 represents optionally substituted lower alkyl
- n is an integer of 1 to 7
- A is represented by the following formula:
- the alkynyl indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3) which is a partial structure represented by (5)
- a medicament comprising the alkynylindazole derivative according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof.
- the medicament according to (5) above which is a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor.
- VEGF vascular endothelial growth factor
- Retinal diseases associated with angiogenesis or edema are age-related macular degeneration, macular edema, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, secondary cataract, myopic choroidal neovascularization, or glaucoma
- the alkynylindazole derivative and its pharmaceutically acceptable salt are not only highly soluble in an aqueous solution, but also excellent in migration to the retina or choroid, as is apparent from the results of Test Example 5 described later. Moreover, it is excellent also in stability, and is especially excellent in light stability in a solution. For this reason, for example, it can be used in the form of liquid preparations such as eye drops and injections.
- the compound of the present invention is an alkynylindazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
- the alkynylindazole derivative represented by the general formula (I) is also referred to as “the present compound (I)”.
- examples of the lower alkyl represented by R 1 include linear, branched or cyclic alkyl having 1 to 4 carbon atoms.
- examples of such lower alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, and cyclobutyl.
- R 1 is preferably linear or branched alkyl having 1 to 3 carbon atoms, more preferably alkyl having 1 or 2 carbon atoms (methyl or ethyl), particularly preferably methyl. .
- X and Y are the same or different and represent CH or N. However, both X and Y are not N.
- X and Y are CH, (ii) X is N, Y is CH, (iii) X is CH, and Y is N be able to.
- X and Y are CH.
- the bonding position of the group represented by Z in the six-membered ring is not particularly limited, and may be any of the ortho, meta, and para positions.
- the bonding position is a position with respect to the ethynyl group.
- Z is preferably bonded to the meta position or the para position, and more preferably bonded to the para position.
- Z is a group represented by the general formula (a).
- the lower alkyl which may have a substituent represented by R 2 includes, for example, linear, branched or cyclic alkyl having 1 to 4 carbon atoms. Can be mentioned. Examples of such lower alkyl include those similar to the lower alkyl represented by R 1 described above.
- R 2 is preferably straight-chain or branched alkyl having 1 to 3 carbon atoms, and more preferably alkyl having 1 or 2 carbon atoms (methyl or ethyl).
- Examples of the lower alkyl substituent which may have a substituent represented by R 2 include hydroxy, amino, dimethylamino, acetylamino, and morpholino.
- Preferable lower alkyl optionally having a substituent represented by R 2 includes, for example, methyl, 2-hydroxyethyl, 2-aminoethyl, 2- (dimethylamino) ethyl, 2-acetylaminoethyl, 2 -(N-morpholino) ethyl can be mentioned, and methyl is more preferred.
- A is a carbamate or ⁇ -alkoxyamide, oxygen in the above formula is bonded to the (poly) ethylene glycol moiety and nitrogen is bonded to the six-membered ring.
- A is preferably the following formula:
- n is an integer of 1 to 7, preferably an integer of 1 to 5, more preferably an integer of 2 to 5, still more preferably 2 to 4, particularly preferably. 3.
- R 1 in the general formula (I) is methyl
- X and Y are CH
- R 2 in the general formula (a) is methyl
- Examples of the pharmaceutically acceptable salt of the compound (I) of the present invention include pharmaceutically acceptable acid addition salts, ammonium salts, and amino acid addition salts.
- One type of salt can be selected and used alone, or two or more types can be used in combination.
- Examples of acid addition salts include salts with inorganic acids and salts with organic acids.
- Examples of salts with inorganic acids include inorganic acid salts such as salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- the salt with an inorganic acid is preferably a hydrochloride, a hydrobromide, or the like, and more preferably a hydrochloride.
- salts with organic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, ascorbine
- Examples thereof include salts with acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, and pantothenic acid.
- the salt with an organic acid is preferably a salt with citric acid, fumaric acid, tartaric acid or the like.
- ammonium salts include methylpyridinium salts and acetylpyridinium salts.
- amino acid addition salts include addition salts of lysine, glycine, alanine, phenylalanine, glutamic acid, aspartic acid, arginine and the like.
- the pharmaceutically acceptable salt is preferably a salt with an inorganic acid or a salt with an organic acid, and more preferably a salt with an inorganic acid.
- Pharmaceutically acceptable salts include solvates such as hydrates.
- the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have an action of inhibiting tyrosine kinase. More specifically, the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have an action of inhibiting VEGF receptor tyrosine kinase such as VEGF receptor 2 tyrosine kinase.
- the compound (I) of the present invention and a pharmaceutically acceptable salt thereof are preferably used as an active ingredient of a VEGF receptor tyrosine kinase inhibitor. Among them, it is particularly suitable as an active ingredient of an inhibitor of VEGF receptor 2 tyrosine kinase.
- VEGF receptor 2 tyrosine kinase inhibitors have an action of inhibiting angiogenesis, and thus are used for the treatment of various diseases or symptoms associated with angiogenesis or edema.
- diseases or symptoms associated with angiogenesis or edema examples include, for example, a disease or symptom in which inhibition of VEGF receptor 2 tyrosine kinase is effective, such as angiogenesis or edema.
- a disease or symptom associated with is suitable.
- diseases or symptoms associated with angiogenesis or edema include, for example, cancer (tumor) (for example, stomach cancer, renal cancer, colon cancer, lung cancer, etc.), retinal disease associated with angiogenesis or edema, angiogenesis or edema. Keratoconjunctival diseases (keratoconjunctivitis, contact lens disorder, etc.), chronic inflammation, rheumatoid arthritis, inflammatory skin diseases, psoriasis, atherosclerosis, myocardial infarction.
- the compound (I) of the present invention and a pharmaceutically acceptable salt thereof are useful as an active ingredient of a medicament used for the prevention or treatment of such diseases or symptoms.
- this invention compound (I) and its pharmaceutically acceptable salt are used suitably for the prevention or treatment of the retinal disease accompanying angiogenesis or edema.
- retinal diseases associated with angiogenesis or edema include age-related macular degeneration, macular edema, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, late cataract, myopic choroidal neovascularization, glaucoma .
- prevention means delaying or preventing the onset of a symptom or disease and its accompanying symptoms, or reducing the risk of a subject developing a symptom or disease.
- Treatment shall mean alleviating or curing a disease or condition and / or its attendant symptoms.
- the present invention also includes a medicament comprising the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof.
- the compound (I) of the present invention and pharmaceutically acceptable salts thereof can be used as they are or in various preparation forms depending on the purpose of administration and the like.
- the medicament of the present invention is usually provided as a pharmaceutical composition comprising the compound (I) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the medicament of the present invention can be used as a VEGF receptor tyrosine kinase inhibitor, particularly preferably as a VEGF receptor 2 tyrosine kinase inhibitor.
- the medicament of the present invention is suitably used for the prevention or treatment of the above-mentioned diseases or symptoms associated with angiogenesis or edema.
- a patient having a disease or symptom associated with the above-mentioned angiogenesis or edema is preferable.
- the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be administered to a mammal that may develop the disease or symptom.
- the present invention also includes a method of inhibiting VEGF receptor tyrosine kinase, wherein the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is administered to a mammal.
- the present invention also prevents or treats diseases or symptoms associated with angiogenesis or edema (preferably retinal diseases associated with angiogenesis or edema), wherein the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof is administered to a mammal. Also encompassed are methods of treatment.
- the medicament of the present invention can be administered orally or parenterally to humans or non-human mammals.
- mammals other than humans include mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep and monkeys.
- the medicament of the present invention for the prevention or treatment of a disease or symptom associated with angiogenesis or edema, it can be usually administered systemically or locally in an oral or parenteral form. It is preferable to select the route of administration that is most effective for treatment.
- parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection or the like.
- parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection or the like.
- parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection or the like.
- parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection or the like.
- parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection or the like.
- parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection or the like.
- parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection or the like.
- parenteral administration such as intravenous injection, subcutaneous
- preparations for parenteral administration for example, injections, ointments, gels, creams, poultices, patches, liniments, suppositories, sprays, inhalants, sprays, eye drops (eye drops), Nasal drops are included.
- the medicament of the present invention when it is applied to an eye disease such as a retinal disease, it is preferably administered parenterally, and particularly preferably administered as an eye drop.
- the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have high solubility in an aqueous solution. Furthermore, this invention compound (I) and its pharmaceutically acceptable salt are excellent in stability in a solution, and are especially excellent in photostability. For this reason, this invention compound (I) and its pharmaceutically acceptable salt can be used conveniently for the formulation containing aqueous solution, Preferably the aqueous solution is used as a base and the formulation which exhibits liquid state is used.
- the compound of the present invention or a pharmaceutically acceptable salt thereof can be suitably used, for example, in preparations such as syrups, injections, eye drops, nasal drops and the like, and particularly suitable as eye drops. is there.
- the medicament of the present invention is known per se in the technical field of pharmaceutical preparations by mixing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier. It can be manufactured according to the method.
- the carrier can be appropriately selected depending on the form of the preparation preferable for administration.
- the content of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the medicine varies depending on the dosage form, dosage, etc., and can be appropriately selected. For example, it can be generally 0.01 to 99.9% by mass, preferably 0.1 to 80% by mass, based on the whole drug.
- various organic or inorganic carrier substances conventionally used as a pharmaceutical material can be used.
- excipients, disintegrants, binders, fluidizing agents, lubricants and the like in solid preparations Solvents, solubilizers, suspending agents, stabilizers, tonicity agents, buffers, thickeners, pH adjusters, soothing agents and the like in liquid preparations can be mentioned.
- additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary.
- the solid preparation may be coated with a coating agent. Only one type of carrier and additive may be used, or two or more types may be used in combination.
- excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, Arabic Rubber.
- disintegrant examples include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and crystalline cellulose.
- binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic.
- Examples of the fluidizing agent include light anhydrous silicic acid and magnesium stearate.
- Examples of the lubricant include magnesium stearate, calcium stearate, and talc.
- Examples of the coating agent include gelatin and sucrose.
- solvent examples include purified water, distilled water for injection, physiological saline, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.
- solubilizer examples include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and polysorbate 80.
- suspending agent examples include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate.
- Examples of the stabilizer include sodium edetate, sodium bisulfite, sodium thiosulfate, sodium citrate, ascorbic acid, and dibutylhydroxytoluene.
- Examples of the isotonic agent include sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, and propylene glycol.
- Examples of the buffer include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, boric acid, and borax.
- Examples of the thickener include hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene glycol.
- Examples of the pH adjuster include hydrochloric acid, citric acid, sodium hydroxide, phosphoric acid, acetic acid, and boric acid.
- Examples of soothing agents include benzyl alcohol.
- Examples of the preservative include benzalkonium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.
- antioxidant examples include sodium sulfite and ascorbic acid.
- colorant examples include food coloring (for example, food red No. 2 or 3) and ⁇ -carotene.
- sweetener examples include saccharin sodium, dipotassium glycyrrhizinate, and aspartame.
- the medicament of the present invention can contain any one or more other medicinal ingredients as long as the effects of the present invention are not impaired.
- the dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the target disease or symptom, administration subject, administration method, etc.
- the dose per administration Is usually 1 ng to 1000 mg, preferably 1 to 200 mg for oral administration. This amount can usually be administered 1 to 4 times a day. In the case of parenteral administration, for example, it is usually 1 ng to 1000 mg, preferably 1 to 200 mg. This amount can usually be administered 1 to 4 times a day.
- eye drops containing usually 0.001 to 10 w / v%, preferably 0.01 to 1 w / v% of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof.
- the agent is preferably instilled 5 to 100 ⁇ L, preferably 30 to 60 ⁇ L at a time about 1 to 6 times a day.
- the manufacturing method of this invention compound (I) is demonstrated.
- the manufacturing method shown below is an example of the manufacturing method of this invention compound (I), However, The manufacturing method of the compound of this invention is not limited to these.
- a protective group is introduced into a functional group as necessary, and deprotection is performed in a post-process; the functional group is treated as a precursor in each step, and a desired functional group is obtained at an appropriate stage.
- Efficient production can also be carried out by devising such as changing the order of each production method and process.
- the process after reaction can be performed by the method performed normally.
- the compound obtained by each process or reaction can be used for the next reaction as a reaction liquid state or a crude product.
- the product can also be isolated from the reaction mixture according to conventional methods. Isolation or purification of the product can be performed by appropriately selecting and combining conventional methods such as crystallization, recrystallization, distillation, liquid separation, and chromatography, as necessary.
- the compound (I) of the present invention can be produced, for example, by the method shown in the following reaction scheme 1 or a method analogous thereto.
- the compound (I) of the present invention comprises a compound represented by the general formula (II) (hereinafter referred to as “compound (II)”) and a compound represented by the formula (III) (hereinafter “compound”) in the presence of a base and a catalyst. (III) ”) can be reacted.
- Compound (II) is generally used in an amount of 0.5 to 3 equivalents, preferably 0.8 to 2 equivalents, relative to compound (III).
- Examples of the base include N, N-diisopropylethylamine, triethylamine, diethylamine, diisopropylamine and the like, and preferably N, N-diisopropylethylamine or triethylamine.
- Such base is generally used in an amount of 1-50 equivalents, preferably 3-30 equivalents, relative to compound (III).
- the catalyst examples include PdCl 2 (PPh 3 ) 2, Pd (PPh 3 ) 4 , copper iodide, copper bromide, etc., preferably PdCl 2 (PPh 3 ) 2 and copper iodide. It can.
- Each of these catalysts is usually used in an amount of 0.01 to 0.5 equivalent, preferably 0.03 to 0.1 equivalent, relative to compound (III).
- This reaction is preferably performed in a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds, and examples thereof include N, N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, ethyl acetate and the like.
- N, N-dimethylformamide or acetonitrile can be mentioned.
- the reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 2 hr to 4 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 25 ° C. to 160 ° C., preferably 60 ° C. to 100 ° C.
- the above compound (II) can be produced by the method shown in the following reaction formula 2 when A in the general formula (a) is urea or carbamate in the group represented by Z.
- a compound represented by the general formula (II-1) (hereinafter referred to as “compound (II-1)”) and a compound represented by the general formula (II-2) (hereinafter referred to as “compound (II-2)”) are included in compound (II).
- TMS represents a trimethylsilyl group.
- Me represents methyl.
- compound (IV-3) The compound represented by the general formula (IV-3) (hereinafter referred to as “compound (IV-3)”) is commercially available, and a commercially available product can be used.
- Compound (IV-3) can be produced according to a method known per se, for example, the method described in WO2013 / 101184 or WO2011 / 092197, or the like, for example, step A described later.
- Step A a compound represented by the general formula (IV-1) (hereinafter referred to as “compound (IV-1)”) is reacted with trimethylsilylacetylene in a solvent in the presence of a base and a catalyst to give a general formula ( IV-2) (hereinafter referred to as “compound (IV-2)”) is produced, and then the trimethylsilyl group of compound (IV-2) is deprotected to produce compound (IV-3). .
- trimethylsilylacetylene is usually used in an amount of 1 to 3 equivalents, preferably 1.2 to 1.5 equivalents, relative to compound (IV-1).
- the base include those similar to the base exemplified in Reaction Scheme 1, and preferably triethylamine.
- Such base is generally used in an amount of 1-30 equivalents, preferably 10-20 equivalents, relative to compound (IV-1).
- the catalyst include the same catalysts as those exemplified in Reaction Scheme 1, and PdCl 2 (PPh 3 ) 2 and copper iodide are preferably used. Each of these catalysts is generally used in an amount of 0.01 to 0.2 equivalent, preferably 0.02 to 0.05 equivalent, relative to compound (IV-1).
- the solvent include the same solvents as those exemplified in Reaction Scheme 1, and tetrahydrofuran can be preferably used. While the reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 3 hr to 4 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 25 ° C. to 120 ° C., preferably 60 ° C. to 90 ° C.
- the compound (IV-3) can be produced by deprotecting the trimethylsilyl group of the obtained compound (IV-2) with a methanol solution to which a base has been added.
- the concentration of the base in the methanol solution is usually 5 to 50 w / v%, preferably 10 to 15 w / v%.
- Examples of such a base include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate and the like, and preferably sodium hydroxide.
- reaction temperature and reaction time for deprotection vary depending on the reagent or solvent used, but the reaction temperature is usually 1 ° C. to 30 ° C., preferably 15 ° C. to 25 ° C., and the reaction time is usually 1 hour to 24 hours. Preferably, it is 2 hours to 4 hours.
- step B compound (IV-3) is reacted with 4-nitrophenyl chloroformate in a solvent to form a carbamate, and then this carbamate and a compound represented by the general formula (V-2) (hereinafter, “ Compound (II-1) ”is produced by reacting Compound (V-2)”.
- Compound (II-1) is produced by reacting Compound (V-2)”.
- 4-Nitrophenyl chloroformate is generally used in an amount of 0.8-10 equivalents, preferably 1-1.3 equivalents, relative to compound (IV-3).
- the solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like. Mention may be made of dichloromethane, tetrahydrofuran or 1,4-dioxane.
- Compound (V-2) is generally used in 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (IV-3).
- reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 48 hr, preferably 2 hr to 24 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 120 ° C., preferably 25 ° C. to 110 ° C.
- Compound (V-2) is commercially available, and a commercially available product can be used.
- Compound (V-2) can be produced according to a method known per se, for example, the method described in WO2009 / 109035 (Japanese Patent Laid-Open No. 2011-105735), or a method analogous thereto, for example, Step C described later. it can.
- step C compound (V-2) is produced from the compound represented by general formula (V-1) (hereinafter referred to as “compound (V-1)”).
- compound (V-1) is reacted with phthalimide, triphenylphosphine and diethyl azodicarboxylate in a solvent (first step).
- the compound (V-2) can be obtained by reacting the product obtained in a solvent with hydrazine monohydrate (second step).
- phthalimide is usually 0.5 to 2 equivalents, preferably 1 to 1.2 equivalents
- triphenylphosphine is usually 0.5 to 2 equivalents, preferably 1 to the compound (V-1).
- diethyl azodicarboxylate is usually used in an amount of 0.5-2 equivalents, preferably 1-1.2 equivalents.
- diethyl azodicarboxylate bis (2-methoxyethyl) azodicarboxylate, diisopropyl azodicarboxylate, cyanomethylene tributylphosphorane, or the like may be used.
- the solvent is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, N, N-dimethylformamide, and preferably tetrahydrofuran.
- reaction time varies depending on the reagent or solvent to be used, it is generally 5 hr to 20 hr, preferably 12 hr to 18 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the product obtained in the first step is usually 0.5 to 3 equivalents, preferably 1 to 2.2 equivalents of hydrazine monohydrate to the compound (V-1) used.
- the solvent is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include methanol, ethanol, isopropanol, and the like, and preferably ethanol.
- the reaction time varies depending on the reagent or solvent to be used, it is generally 2 hr to 20 hr, preferably 4 hr to 18 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 25 ° C. to 120 ° C., preferably 80 ° C. to 100 ° C.
- Step D compound (V-1) is reacted with di (N-succinimidyl) carbonate in the presence of a base to form a carbonate form in a solvent, and then the carbonate form and compound (IV-3) are condensed to form a compound.
- (II-2) is produced.
- the base is usually used in an amount of 0.5 to 5 equivalents, preferably 2 to 3.5 equivalents, relative to compound (V-1), and di (N-succinimidyl) carbonate is usually used in an amount of 0.5 to 5 equivalents, preferably 1 to Two equivalents are used.
- di (N-succinimidyl) carbonate bis (trichloromethyl) carbonate, 1,1'-carbonyldiimidazole, 4-nitrophenyl chloroformate, phenyl chloroformate and the like may be used.
- the base include triethylamine, tributylamine, pyridine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, and preferably triethylamine.
- a reaction accelerator examples include 4-dimethylaminopyridine, 4-pyrrolidinopyridine, and preferably 4-dimethylaminopyridine.
- the reaction accelerator is generally used in an amount of 0.05 to 0.5 equivalents, preferably 0.1 to 0.2 equivalents, relative to compound (V-1). Furthermore, compound (V-1) is generally used in an amount of 0.5-5 equivalents, preferably 1-2 equivalents, relative to compound (IV-3).
- the solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, N, N-dimethylformamide, and preferably ethyl acetate is used. Can be mentioned.
- reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 48 hr, preferably 10 hr to 24 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 100 ° C., preferably 60 ° C. to 80 ° C.
- the compound (II) can be produced by, for example, the method shown in the following reaction formula 3 when A in the general formula (a) is an ⁇ -alkoxyamide or amine in the group represented by Z. it can.
- a compound represented by the general formula (II-3) (hereinafter referred to as “compound (II-3)”) and a compound represented by the general formula (II-4) (hereinafter referred to as “compound (II-4)”)
- compound (II-3) a compound represented by the general formula (II-3)
- compound (II-4) hereinafter referred to as “compound (II-4)
- Ts represents a p-toluenesulfonyl group (tosyl group).
- Me represents methyl and tBu represents tert-butyl.
- Step E the compound (V-1) is reacted with tert-butyl bromoacetate in the presence of a base in a normal solvent, and then the compound represented by the general formula (V-3) is obtained by ester hydrolysis.
- compound (V-3) is produced.
- the base is usually used in an amount of 1 to 5 equivalents, preferably 2 to 3 equivalents
- tert-butyl bromoacetate is usually used in an amount of 1 to 3 equivalents, preferably 1 to 1.2 equivalents, relative to compound (V-1).
- Examples of such a base include sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, n-butyllithium and the like, and preferably sodium hydride.
- a base instead of tert-butyl bromoacetate, methyl chloroacetate, ethyl chloroacetate, methyl bromoacetate, ethyl bromoacetate or the like may be used.
- the solvent is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include N, N-dimethylformamide, toluene, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, and the like, and preferably tetrahydrofuran.
- reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 10 hr to 17 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 100 ° C., preferably 0 ° C. to 25 ° C.
- the hydrolysis of the ester is usually performed in a solvent in the presence of a base.
- the base is generally used in an amount of 1 to 5 equivalents, preferably 2 to 4 equivalents, relative to the ester.
- examples of such a base include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and preferably lithium hydroxide.
- the solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include a mixed solvent of an organic solvent (eg, acetonitrile, 1,4-dioxane, tetrahydrofuran, etc.) and water, preferably a mixed solvent of tetrahydrofuran and water. Can be mentioned.
- reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 3 hr to 5 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 100 ° C., preferably 60 ° C. to 100 ° C.
- step F compound (II-3) is produced by reacting compound (V-3) and compound (IV-3) in the presence of a base and a condensing agent in a normal solvent.
- Compound (V-3) is usually used in an amount of 0.1 to 3 equivalents, preferably 0.5 to 1.2 equivalents, relative to compound (IV-3).
- the condensing agent is generally used in an amount of 1 to 3 equivalents, preferably 1 to 2 equivalents, and the base used in an amount of 0.5 to 5 equivalents, preferably 2 to 4 equivalents, relative to compound (IV-3).
- condensing agent examples include N, N′-dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride, benzotriazol-1-yloxy Tripyrrolidinophosphonium hexafluorophosphate, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, trifluoroacetic acid pentafluorophenyl ester, isopropyl chloroformate, etc.
- the base include triethylamine, pyridine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, and preferably triethylamine, N, N-diisopropylethylamine, or 4-dimethylaminopyridine.
- the solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, acetonitrile, N, N-dimethylformamide and the like. Preferred examples include dichloromethane or N, N-dimethylformamide.
- the reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 3 hr to 24 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 100 ° C., preferably 25 ° C. to 40 ° C.
- Step G first, compound (V-1) is reacted with p-toluenesulfonyl chloride in the presence of a base in a normal solvent to give a compound represented by general formula (V-4) (hereinafter referred to as “compound (V— 4) ").
- compound (V— 4) is reacted with compound (IV-3) in the presence of a base in a normal solvent to produce compound (II-4).
- p-Toluenesulfonyl chloride is generally used in 1 to 2.2 equivalents, preferably 1.2 to 1.5 equivalents, relative to compound (V-1).
- the base is generally used in 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to compound (V-1).
- Examples of such a base include pyridine, triethylamine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, and preferably triethylamine.
- the solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and preferably dichloromethane.
- the reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 14 hr to 21 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 100 ° C., preferably 25 ° C. to 50 ° C.
- the compound (V-4) is usually used in an amount of 0.3 to 5 equivalents, preferably 0.5 to 5 with respect to the compound (IV-3).
- the base is generally used in 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to compound (IV-3). Examples of such a base include sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate and the like, and preferably cesium carbonate or potassium carbonate.
- a reaction accelerator is preferably used. Such a reaction accelerator is usually used in an amount of 0.1 to 3 equivalents, preferably 0.2 to 1 equivalents, relative to compound (IV-3).
- reaction accelerator examples include sodium iodide, potassium iodide, tetrabutylammonium iodide and the like, and preferably potassium iodide.
- the solvent is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include acetonitrile, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, dimethyl sulfoxide and the like, preferably acetonitrile or N, N-dimethylformamide. Can do.
- reaction time varies depending on the reagent or solvent to be used, it is generally 9 hr to 60 hr, preferably 18 hr to 24 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 25 ° C. to 120 ° C., preferably 80 ° C. to 120 ° C.
- Compound (II-4) is a compound represented by the general formula (VI) represented by Step G ′ in Reaction Scheme 3 instead of Compound (V-4) in the reaction of Compound (V-4) and Compound (IV-3). ) (Hereinafter referred to as “compound (VI)”).
- Preferred conditions for the reaction of the compound (VI) and the compound (IV-3) according to Step G ′ are the same as those of the compound (V-4) and the compound (IV-3) according to Step G described above.
- Compound (III) is a known method, for example, the method described in WO2006 / 048745 (Japanese Patent Publication No. 2008-518901), WO2001 / 002369 (Patent No. 3788849), or the like, for example, according to the following reaction scheme 4. Can be manufactured.
- Me represents methyl.
- a compound represented by formula (VII-1) (hereinafter referred to as “compound (VII-1)”) is reacted with oxalyl chloride in a usual solvent to obtain a compound represented by formula (VII-2).
- An acid chloride represented by the formula (VII-3) by reacting with an acid chloride (hereinafter referred to as “acid chloride (VII-2)”) and then reacting with methylamine. (VII-3) ”).
- a thiol compound represented by the formula (VII-4) (hereinafter referred to as “thiol compound (VII-4)”) is obtained by reducing the amide compound represented by the formula (VII-3) with sodium borohydride. Can be obtained.
- Oxalyl chloride is generally used in an amount of 1 to 5 equivalents, preferably 2 to 4 equivalents, relative to compound (VII-1).
- the solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include tetrahydrofuran, dichloromethane, toluene and the like, preferably dichloromethane.
- a reaction accelerator is preferably used in the reaction of compound (VII-1) and oxalyl chloride.
- Such a reaction accelerator is usually used in an amount of 0.01 to 0.5 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound (VII-1).
- An example of the reaction accelerator is N, N-dimethylformamide.
- reaction time varies depending on the solvent to be used, it is generally 10 hr to 60 hr, preferably 15 hr to 40 hr.
- reaction temperature varies depending on the solvent, it is generally 15 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C.
- the reaction between acid chloride (VII-2) and methylamine can be carried out, for example, in tetrahydrofuran.
- Methylamine is usually used in an amount of 1 to 5 equivalents, preferably 2 to 5 equivalents, relative to acid chloride (VII-2).
- the reaction time is usually 6 hours to 24 hours, preferably 12 hours to 24 hours.
- the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C.
- sodium borohydride is usually used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to the amide compound (VII-3).
- the reaction can be performed, for example, in ethanol.
- the reaction time is usually 6 hours to 24 hours, preferably 12 hours to 20 hours.
- the reaction temperature is usually 0 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.
- a compound represented by the formula (VIII-1) (hereinafter referred to as “compound (VIII-1)”) is reacted with sodium nitrite and then potassium iodide in an acidic aqueous solution to obtain the formula (VIII-2). ) (Hereinafter referred to as “compound (VIII-2)”).
- compound (VIII-2) was synthesized in the presence of thiol form (VII-4), Pd 2 (dba) 3 , 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene and cesium hydroxide monohydrate.
- a compound represented by the formula (VIII-3) (hereinafter referred to as “compound (VIII-3)”).
- the compound (III-3) can be produced by iodination of the compound (VIII-3) in the presence of potassium carbonate.
- sodium nitrite is usually used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII-1).
- Potassium is usually used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents.
- the reaction time with the compound (VIII-1) and sodium nitrite is usually 10 minutes to 6 hours, preferably 0.5 hours to 2 hours.
- the reaction temperature is usually 0 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.
- the reaction time with potassium iodide is usually 10 minutes to 6 hours, preferably 0.5 hours to 3) hours.
- the reaction temperature is usually 0 ° C. to 50 ° C., preferably 0 ° C. to 40 ° C.
- the reaction for obtaining the compound (VIII-3) from the compound (VIII-2) and the thiol form (VII-4) can be carried out in an argon gas atmosphere, for example, in N, N-dimethylformamide.
- the thiol compound (VII-4) is generally used in 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII-2).
- Pd 2 (dba) 3 is generally used in an amount of 0.01 to 3 equivalents, preferably 0.03 to 1 equivalents, relative to compound (VIII-2).
- 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene is generally used in an amount of 0.05 to 3 equivalents, preferably 0.1 to 2 equivalents, relative to compound (VIII-2).
- Cesium hydroxide monohydrate is usually used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII-2).
- the reaction time is usually 1 hour to 24 hours, preferably 2 hours to 10 hours.
- the reaction temperature is usually from 25 ° C to 150 ° C, preferably from 80 ° C to 120 ° C.
- the iodination of the compound (VIII-3) can be performed, for example, in N, N-dimethylformamide.
- Potassium carbonate is generally used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII-3).
- Iodine is generally used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII-3).
- the reaction time is usually 1 hour to 24 hours, preferably 1 hour to 6 hours. Usually, it is 0 ° C to 50 ° C, preferably 0 ° C to 30 ° C.
- the above compound (II) is represented by the following reaction formula 5 when A in the general formula (a) is urea and R 2 is optionally substituted lower alkyl in the group represented by Z. It can be manufactured by a method.
- a compound represented by formula (II-5) (hereinafter referred to as “compound (II-5)”), a compound represented by formula (II-6) (hereinafter referred to as “compound (II-6)”), A compound represented by formula (II-7) (hereinafter referred to as “compound (II-7)”), a compound represented by formula (II-8) (hereinafter referred to as “compound (II-8)”), And the compound represented by the formula (II-9) (hereinafter referred to as “compound (II-9)”) is encompassed in the compound (II).
- Ts represents a p-toluenesulfonyl group (tosyl group), and Me represents methyl.
- a compound represented by formula (V-5) is converted from a compound represented by formula (VI-2) (hereinafter referred to as “compound (VI-2)”) (hereinafter referred to as “compound (V-5)”). ").
- compound (VI-2) is reacted with tert-butyldimethylchlorosilane in a solvent in the presence of a base (first step).
- the product obtained in the solvent is reacted with phthalimide, triphenylphosphine, and diethylazodicarboxylate (second step).
- compound (V-5) can be obtained by reacting the resulting product with hydrazine monohydrate and then with hydrochloric acid (third step).
- the base is usually 0.8 to 1.2 equivalents, preferably 1 to 1.1 equivalents, and tert-butyldimethylchlorosilane 0.8 to 2 equivalents, relative to compound (VI-2).
- 1 to 1.2 equivalents are used.
- Examples of such a base include sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, n-butyllithium and the like, and preferably sodium hydride.
- the solvent is not particularly limited, and examples thereof include N, N-dimethylformamide, toluene, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like, preferably tetrahydrofuran.
- reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 48 hr, preferably 15 hr to 24 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 100 ° C., preferably 0 ° C. to 25 ° C.
- the phthalimide is usually 0.5 to 2 equivalents, preferably 1 to 1.6 equivalents
- triphenylphosphine is usually 1 to 2 equivalents, preferably the product obtained in the first step.
- diethyl azodicarboxylate is usually used in 1 to 2 equivalents, preferably 1 to 1.2 equivalents.
- diethyl azodicarboxylate bis (2-methoxyethyl) azodicarboxylate, diisopropyl azodicarboxylate, cyanomethylene tributylphosphorane, or the like may be used.
- the solvent is not particularly limited, and examples include dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, N, N-dimethylformamide, and preferably tetrahydrofuran.
- reaction time varies depending on the reagent or solvent to be used, it is generally 5 hr to 20 hr, preferably 12 hr to 18 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- hydrazine monohydrate is usually used in an amount of 1 to 5 equivalents, preferably 1 to 4.4 equivalents, relative to the product obtained in the second step.
- a solvent For example, methanol, ethanol, isopropanol etc. are mentioned, Preferably ethanol can be mentioned.
- reaction time varies depending on the reagent or solvent to be used, it is generally 2 hr to 20 hr, preferably 4 hr to 18 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 25 ° C. to 120 ° C., preferably 80 ° C. to 100 ° C.
- concentrated hydrochloric acid is added in an amount of 5 to 10 equivalents, preferably 8 to 10 equivalents.
- reaction time varies depending on the solvent to be used, it is generally 2 hr to 20 hr, preferably 2 hr to 4 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 120 ° C., preferably 90 ° C. to 110 ° C.
- Step I a compound represented by formula (V-6) (hereinafter referred to as “compound (V-6)”) to a compound represented by formula (V-7) (hereinafter referred to as “compound (V-7)”) ").
- compound (V-6) is reacted with di-tert-butyl dicarbonate in a solution (first step).
- the product obtained in the solvent is reacted with formaldehyde, acetic acid, and sodium triacetoxyborohydride (second step).
- compound (V-7) can be obtained by reacting the obtained product with trifluoroacetic acid in a solution (third step).
- di-tert-butyl dicarbonate (30% tetrahydrofuran solution) is usually 0.4 to 0.6 equivalents, preferably 0.5 to 0.6 equivalents, relative to compound (V-6).
- diisopropylethylamine is used in an amount of 0.8 to 1.1 equivalents, preferably 0.9 to 1.0 equivalents.
- the solvent is not particularly limited, and examples thereof include tetrahydrofuran, dichloromethane, chloroform, acetonitrile, 1,4-dioxane, and preferably dichloromethane.
- the reaction time varies depending on the reagent or solvent to be used, it is generally 2 hr to 10 hr, preferably 2 hr to 4 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- formaldehyde (37% aqueous solution) is usually 10 to 40 equivalents, preferably 20 to 30 equivalents
- acetic acid is usually 10 to 40 equivalents, preferably 20 to the product obtained in the first step.
- a solvent For example, methanol, ethanol, isopropanol etc. are mentioned, Preferably methanol can be mentioned.
- the reaction time varies depending on the reagent or solvent to be used, it is generally 2 hr to 10 hr, preferably 2 hr to 3 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the third step 5 to 20 equivalents, preferably 5 to 17 equivalents, of trifluoroacetic acid is used with respect to the product obtained in the second step.
- the solvent is not particularly limited, and examples thereof include tetrahydrofuran, dichloromethane, chloroform, acetonitrile, 1,4-dioxane, and preferably dichloromethane can be used.
- the reaction time varies depending on the reagent or solvent to be used, it is generally 30 min to 2 hr, preferably 30 min to 1 hr.
- the reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- step J compound (II-8) is produced by reacting compound (II-7) with acetic anhydride in a normal solvent.
- 1 to 5 equivalents, preferably 1.5 to 3 equivalents of acetic anhydride, and 0.1 to 0.5 equivalents, preferably 0.1 to 0, of 4-dimethylaminopyridine with respect to compound (II-7). .3 equivalents are used.
- the solvent is not particularly limited, and examples thereof include tetrahydrofuran, dichloromethane, chloroform, acetonitrile, 1,4-dioxane, and preferably acetonitrile can be used.
- reaction time varies depending on the reagent or solvent to be used, it is generally 6 hr to 10 hr, preferably 6 hr to 8 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- Step K a compound represented by the formula (VI-3) (hereinafter referred to as “compound (VI-3)”) is reacted with p-toluenesulfonyl chloride in a normal solvent in the presence of a base, to give a compound of the formula (VI -4) (hereinafter referred to as “compound (VI-4)”).
- P-Toluenesulfonyl chloride is generally used in 2 to 3 equivalents, preferably 2 to 2.2 equivalents, relative to compound (VI-3).
- the base is generally used in 2 to 8 equivalents, preferably 5 to 8 equivalents, relative to compound (VI-3).
- Examples of such base include sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate and the like, and preferably potassium hydroxide or sodium hydroxide.
- Examples of the solvent include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and preferably dichloromethane. While the reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 3 hr to 10 hr. While the reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- step L compound (II-9) is produced by reacting compound (II-7) with compound (VI-4) in the presence of a base in a normal solvent.
- Compound (VI-4) is generally used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents, and the base 1 to 3 equivalents, preferably 1.5 to 2 equivalents, relative to compound (II-7).
- Examples of such base include sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate and the like, and preferably potassium carbonate or sodium carbonate.
- the solvent include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and preferably acetonitrile.
- reaction time varies depending on the reagent or solvent to be used, it is generally 10 hr to 24 hr, preferably 10 hr to 18 hr.
- reaction temperature varies depending on the reagent or solvent to be used, it is generally 25 ° C. to 120 ° C., preferably 80 ° C. to 100 ° C.
- step B ′ compound (II-5) is prepared by using compound (V-5), (V-6), or (V-7) instead of compound (V-2) in the same manner as in step B. ), (II-6), or (II-7).
- the produced compound (I) of the present invention can be isolated or purified as a free form or subjected to salt formation treatment by a conventional method, and as a salt thereof.
- the isolation or purification method is not particularly limited, and for example, commonly used methods such as crystallization, recrystallization, distillation, liquid separation, and chromatography can be appropriately selected and combined.
- the solvate of the compound (I) of the present invention can be obtained according to a method known per se.
- the melting point was measured using MP-500V type (no correction) manufactured by Yanaco.
- 1 H-NMR spectra were recorded on a Bruker instrument operating at 400 MHz.
- NMR spectra were obtained as CDCl 3 solutions using chloroform as a reference standard (7.26 ppm) or tetramethylsilane (0.00 ppm) inside as appropriate. Other NMR solvents were used as needed.
- Phthalimide (5.59 g, 38 mmol), triphenylphosphine (10.3 g, 39.2 mmol), triethylene glycol monomethyl ether (6 mL, 38.4 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution) (18.2 mL, 40 mmol), tetrahydrofuran (150 mL), ethanol (220 mL), and hydrazine monohydrate (3 mL, 84.5 mmol) were used as starting materials and the same procedure as in Reference Example 7 was performed to give the title compound (4.48 g, 72%) was obtained as a yellow oil.
- Triethylene glycol monomethyl ether (824.3 mg, 5.0 mmol), ethyl acetate (4 mL), di (N-succinimidyl) carbonate (1.37 g, 5.3 mmol), triethylamine (2.0 mL, 14 mmol), and 4-ethynylaniline ( The title compound (1.21 g, 79%) was obtained as a yellow oil by the same procedure as in Reference Example 29 using 744.2 mg, 6.4 mmol) as a starting material.
- Tetraethylene glycol monomethyl ether (1.53 g, 7.4 mmol), ethyl acetate (10 mL), di (N-succinimidyl) carbonate (2.11 g, 8.2 mmol), triethylamine (3.0 mL, 22 mmol), and 4-ethynylaniline ( The title compound (1.54 g, 60%) was obtained as an orange oil in the same manner as in Reference Example 29 using 1.12 g, 9.5 mmol) as a starting material.
- Pentaethylene glycol monomethyl ether (1.54 g, 6.1 mmol), ethyl acetate (10 mL), di (N-succinimidyl) carbonate (1.77 g, 6.9 mmol), triethylamine (2.6 mL, 19 mmol), 4-ethynylaniline (962.2 mg, 8.2 mmol) and 4-dimethylaminopyridine (78.5 mg, 0.64 mmol) were used as starting materials and were treated in the same manner as in Reference Example 29 to give the title compound (1.20 g, 50%) as an orange oil. .
- Tetraethylene glycol monomethyl ether (3.04 g, 19 mmol) was added to a solution of 60% sodium hydride (1.37 g, 34 mmol) in tetrahydrofuran (10 mL) under ice cooling, and the mixture was stirred for 20 minutes.
- tert-butyl bromoacetate (4.31 g, 22 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 13 hours.
- lithium hydroxide (1.73 g, 72 mmol) and water (15 mL) were further added, and the mixture was stirred for 4 hours under heating to reflux.
- the solution was diluted with water and washed with diethyl ether.
- reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure to obtain the title compound (218.2 mg, 77%) as an orange oil.
- 3,6,9,12-Tetraoxatridecanoic acid 320.1 mg, 1.4 mmol was added to 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (526.1 mg, 2.7 mmol), 4- Dimethylaminopyridine (664.6 mg, 5.4 mmol), dichloromethane (5 mL), and 5-ethynylpyridin-2-amine (239.6 mg, 2.0 mmol) were added, and the mixture was stirred overnight at room temperature.
- reaction solution was diluted with ethyl acetate, washed with 10% aqueous citric acid solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Triethylamine (1.27 mL, 9.15 mmol) and triethylene glycol monomethyl ether (525 ⁇ L, 3.05 mmol) were added to a solution of p-toluenesulfonyl chloride (872.2 mg, 4.58 mmol) in dichloromethane (3 mL), and the mixture was stirred overnight at room temperature. .
- Methanol (0.5 mL) was further added to this solution, and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, the insoluble material was removed by filtration, and the insoluble material was washed with diethyl ether and isopropanol.
- 6-iodo-1H-indazole (5.51 g, 22 mmol), 2-mercapto-N-methylbenzamide (5.16 g, 31 mmol), Pd 2 (dba) 3 (1.02 g, 1.1 mmol), 4,5-bis N, N-dimethylformamide (25 mL) was added to (diphenylphosphino) -9,9-dimethylxanthene (1.46 g, 2.5 mmol) and cesium hydroxide monohydrate (5.67 g, 33 mmol), The mixture was stirred at 100 ° C. for 4.5 hours under an argon atmosphere.
- Triethylene glycol (2.2 mL, 16.5 mmol) was added to a tetrahydrofuran (88 mL) solution of 60% sodium hydride (713 mg, 17.8 mmol) at 0 ° C., and the mixture was stirred at room temperature for 40 minutes.
- tert-butyldimethylchlorosilane (2.74 g, 18.2 mmol) was stirred at room temperature for 23 hours.
- Water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.19 g, quant.) As a pale yellow oil.
- 1 H NMR 400 MHz, CDCl 3 ) ⁇ 3.79-3.72 (4H, m), 3.67-3.54 (8H, m), 0.90 (9H, s), 0.07 (6H, s).
- Acetic anhydride 48.2 ⁇ L, 0.51 in 1- ⁇ 2- [2- (2-aminoethoxy) ethoxy] ethyl ⁇ -3- (4-ethynylphenyl) urea (100 mg, 0.34 mmol) in acetonitrile (2 mL) mmol) and 4-dimethylaminopyridine (8.3 mg, 0.068 mmol) were added and stirred at room temperature for 8 hours, and then the solvent was distilled off under reduced pressure.
- Formulation Example A pharmaceutical containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
- Capsule (1) Compound 1 40mg (2) Lactose 70mg (3) Microcrystalline cellulose 9mg (4) Magnesium stearate 1mg 1 capsule 120mg The whole amount of (1), (2), (3) and 1/2 of (4) are mixed and granulated. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
- Tablet (1) Compound 1 40mg (2) Lactose 58mg (3) Corn starch 18mg (4) Microcrystalline cellulose 3.5mg (5) Magnesium stearate 0.5mg 1 tablet 120mg The whole amount of (1), (2) and (3), 2/3 of (4) and 1/2 of (5) are mixed and granulated. The remaining (4) and (5) are added to the granules and pressed into tablets.
- Eye drops (1) Compound 1 0.1 g (2) Sodium dihydrogen phosphate dihydrate 0.35mg (3) Sodium chloride 0.5mg (4) Benzalkonium chloride 0.005g (5) Sodium hydroxide appropriate amount (pH 7) (6) Sterilized purified water, 100 mL (1), (2), (3), (4), (5) and 90 mL of (6) are aseptically mixed, and then an appropriate amount of (6) is added to prepare an eye drop.
- Compounds 1-41 produced in Examples were used as test substances.
- the kinase inhibitory activity of each compound produced in the examples was measured using Off-chip Mobility Shift Assay.
- human recombinant VEGF receptor 2 was produced with a baculovirus expression system.
- the recombinant protein was expressed as a GST fusion protein by using the cytoplasmic domain 790-1356 amino acids of VEGF receptor 2 (NP_002244.1) and binding glutathione-S-transferase (GST) to its N-terminus. .
- the expressed GST-VEGF receptor 2 fusion protein was purified using glutathione sepharose chromatography. Further, a test substance was dissolved in dimethyl sulfoxide to prepare a solution having a concentration 100 times the test concentration. Further, the solution was diluted 25-fold with an assay buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH 7.5) to obtain a 4-fold concentration test substance solution. CSKtide was used as a substrate in the kinase inhibition assay.
- the kinase reaction was carried out using 10 mL of 2 ⁇ VEGF receptor 2 kinase solution, 5 mL of 4 ⁇ test substance solution prepared in assay buffer, and 5 mL of 4 ⁇ substrate / ATP / metal solution in 384-well polypropylene.
- the mixture was mixed in the well of the plate and reacted at room temperature for 1 hour (substrate concentration: CSKtide 1000 nM, ATP concentration: 75 ⁇ M, Magnesium: 5 mM).
- 60 mL of Termination Buffer Quality of phosphate
- a VEGF receptor 2 kinase inhibition assay was performed in the same manner as described above using the following compound A and compound B.
- the results are shown in Table 2.
- Compound A 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] indazole (generic name: axinitiv)
- Compound B 6- [2- (Methylcarbamoyl) phenylsulfanyl] -3- [2- (pyridin-2-yl) ethynyl] indazole
- Compound A was purchased by using axitinib (catalog number: 4350) manufactured by Tocris Bioscience did.
- Compound B was synthesized according to the method described in Example 20 of WO2006 / 048745.
- hRMVE human retinal microvascular endothelial
- hRMVEC human retinal microvascular endothelial cells
- ACBRI 181 Human retinal microvascular endothelial cells
- An adhesion factor solution (Cell Systems, Attachment Factor) was added to a 96-well plate (manufactured by Iwaki Glass Co., Ltd.).
- hRMVEC cells suspended in CS-C medium (Cell System, CS-C medium kit, catalog number: CS-4ZO-500R) containing serum, growth factors, and Culture Boost are 2 ⁇ 10
- CS-C medium Cell System, CS-C medium kit, catalog number: CS-4ZO-500R
- Culture Boost Culture Boost
- the cells were seeded at a density of 3 cells / 100 ⁇ L / well and cultured at 37 ° C. under 5% CO 2 for 1 day. Thereafter, the medium is removed from hRMVEC, washed twice with PBS, and then CS-C medium containing 1% FBS and growth factors (Cell System, CS-C medium kit, catalog number: CS-4Z3-500R) And cultured for 6 hours.
- CS-C medium containing recombinant human VEGF Becton Dickinson Co., Ltd.
- Cell System, CS-C medium kit, catalog number: CS -4ZO-500S Cell System, CS-C medium kit, catalog number: CS -4ZO-500S
- the number of cells was measured by the MTT assay (manufactured by Dojindo Laboratories: Cell Counting Kit-8), and the growth inhibition rate of hRMVEC by the compound was calculated from the following formula.
- Cell growth inhibition rate (%) 100-100 ⁇ (absorbance in wells added with VEGF and compound-absorbance in wells without VEGF) / (absorbance in wells added with VEGF-absorbance in wells without VEGF)
- IC50 (M) 100-100 ⁇ (absorbance in wells added with VEGF and compound-absorbance in wells without VEGF) / (absorbance in wells added with VEGF-absorbance in wells without VEGF)
- IC50 (M) 100-100 ⁇ (absorbance in wells added with VEGF and compound-absorbance in wells without VEGF) / (absorbance in wells added with VEGF-absorb
- IC50 (M) 10 ⁇ (LOG (A / B) ⁇ (50-C) / (DC) + LOG (B))
- Table 3 shows the hRMVE cell growth inhibitory activity of typical compounds among the compounds produced in the examples.
- the compound A and compound B used in Test Example 1 were similarly measured for hRMVE cell proliferation inhibitory activity, and the results are shown in Table 3.
- ⁇ Test Example 4> Photostability test After dissolving 1.00 mg of the compound produced in the example in 10 mL of methanol, the sample was diluted with a water / methanol mixed solution (v / v 1: 1) to obtain a 10 ⁇ g / mL sample. A solution was prepared. The sample was allowed to stand for 6 hours under a white fluorescent lamp (500 Lux) and then analyzed by HPLC to determine the residual ratio (%) of the compound. The analysis conditions of HPLC are as follows. As a reference example, the same experiment was performed for Compound A used in Test Example 1. The residual ratio (light stability) is shown in Table 5. The compounds prepared in the examples were stable to light in solution.
- ⁇ Test Example 5 Drug transferability test to retina / choroid
- the ophthalmic solution used in this test was prepared by suspending Compound 8, Compound 27 or Compound A in a phosphate buffer (pH 7.0) so that the drug concentration was 0.25% according to a conventional method.
- eye drops were administered to rabbits (Japanese white rabbits) at 50 ⁇ L per eye, and the rabbits were euthanized 2 hours after the eye drops were administered, and the eyeballs were removed.
- the extracted eyeball was frozen with liquid nitrogen, divided into two at the equator plane, and then the retina / choroid tissue was collected from the posterior eye side.
- the tissue was finely cut in methanol to prepare a lysate, and then the lysate was centrifuged and the supernatant was collected.
- An equal amount of ultrapure water was added to the combined extraction solution of the supernatant, and the solution was filtered with a membrane filter (0.22 ⁇ m), which was used as the final measurement solution.
- the drug concentration of the filtrate was analyzed by liquid chromatography mass spectrometry (LC / MS / MS), and the compound concentration in the retina / choroid tissue was calculated from the peak area value obtained using the external standard method.
- the analysis conditions for LC / MS / MS are as follows.
- Table 6 shows the average compound concentration in the retina / choroid.
- the compound concentration of the retina / choroid was subjected to a rejection test using JMP (registered trademark) (SAS Institute Institute Inc.), and outliers were excluded, and then the average value ⁇ standard deviation was used.
- the compound (I) of the present invention and a pharmaceutically acceptable salt thereof are compounds useful as inhibitors of the VEGF receptor, and are useful for the prevention or treatment of various diseases or symptoms involving the receptor.
- the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have high solubility in an aqueous solution and are excellent in stability in a solution state. Therefore, the compound (I) and a pharmaceutically acceptable salt thereof can be used, for example, in the form of a liquid such as eye drops. Can do.
- the compound (I) of the present invention and a pharmaceutically acceptable salt thereof are useful as a medicament for the prevention or treatment of retinal diseases associated with angiogenesis or edema.
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Abstract
Description
本発明はまた、VEGF受容体チロシンキナーゼ阻害活性を有し、かつ水溶液に対する溶解度が高く、安定性に優れる化合物を提供することも課題とする。 The main object of the present invention is to provide a novel compound having VEGF receptor tyrosine kinase inhibitory activity and useful as a therapeutic agent for diseases associated with angiogenesis or edema such as age-related macular degeneration.
Another object of the present invention is to provide a compound having VEGF receptor tyrosine kinase inhibitory activity, high solubility in an aqueous solution, and excellent stability.
下記一般式(I)で表されるアルキニルインダゾール誘導体及びその塩は、上述したようにVEGF受容体チロシンキナーゼ阻害活性を有し、かつ水溶液に対する溶解度が向上したものであり、さらに溶液中での光安定性に優れるため、点眼剤等の液剤に好適に使用することができるものである。 Axitinib marketed as an oral antineoplastic agent is an excellent VEGF receptor inhibitor having VEGF receptor tyrosine kinase inhibitory activity. When the present inventors tested whether axitinib can be applied to a liquid preparation such as eye drops, it was predicted that the solubility in an aqueous solution was low and the transferability to the posterior segment was not sufficient. It was also found that axinitib has poor photostability in aqueous solution. From these viewpoints, it has been difficult to apply axitinib to liquid preparations such as eye drops.
The alkynylindazole derivative represented by the following general formula (I) and a salt thereof have a VEGF receptor tyrosine kinase inhibitory activity as described above, and have improved solubility in an aqueous solution. Since it is excellent in stability, it can be suitably used for liquid preparations such as eye drops.
(1)下記一般式(I): Examples of the present invention include the following alkynylindazole derivatives or pharmaceutically acceptable salts thereof, and pharmaceuticals containing the same.
(1) The following general formula (I):
(式中、R2は置換基を有していてもよい低級アルキルを表し、nは1~7の整数であり、Aは、下記式:
(Wherein R 2 represents optionally substituted lower alkyl, n is an integer of 1 to 7, and A is represented by the following formula:
(2)X及びYがともにCHである、前記(1)に記載のアルキニルインダゾール誘導体、又はその医薬上許容される塩。
(3)Zがパラ位に結合している、前記(1)又は(2)に記載のアルキニルインダゾール誘導体、又はその医薬上許容される塩。
(4)Aが、下記式: An alkynylindazole derivative represented by the above formula, or a pharmaceutically acceptable salt thereof.
(2) The alkynylindazole derivative or the pharmaceutically acceptable salt thereof according to (1), wherein X and Y are both CH.
(3) The alkynylindazole derivative or the pharmaceutically acceptable salt thereof according to (1) or (2), wherein Z is bonded to the para position.
(4) A is the following formula:
(5)前記(1)~(4)のいずれか一項に記載のアルキニルインダゾール誘導体、又はその医薬上許容される塩を含むことを特徴とする医薬。
(6)血管内皮細胞増殖因子(VEGF)受容体チロシンキナーゼ阻害剤である、前記(5)に記載の医薬。
(7)血管新生又は浮腫を伴う網膜疾患の予防又は治療用医薬である、前記(5)又は(6)に記載の医薬。
(8)血管新生又は浮腫を伴う網膜疾患が、加齢性黄斑変性症、黄斑浮腫、糖尿病性網膜症、未熟児網膜症、網膜静脈閉塞症、後発白内障、近視性脈絡膜新生血管、又は緑内障である、前記(7)に記載の医薬。 The alkynyl indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3), which is a partial structure represented by
(5) A medicament comprising the alkynylindazole derivative according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof.
(6) The medicament according to (5) above, which is a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor.
(7) The medicament according to (5) or (6) above, which is a medicament for the prevention or treatment of retinal diseases associated with angiogenesis or edema.
(8) Retinal diseases associated with angiogenesis or edema are age-related macular degeneration, macular edema, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, secondary cataract, myopic choroidal neovascularization, or glaucoma The pharmaceutical according to (7) above.
本発明において、 The compound of the present invention is an alkynylindazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof. In the present specification, the alkynylindazole derivative represented by the general formula (I) is also referred to as “the present compound (I)”.
In the present invention,
一般式(a)において、Aは、好ましくは、下記式: Is a partial structure represented by The partial structures represented by the above formulas are referred to as urea, carbamate, α-alkoxyamide, and amine, respectively. The left side of the partial structures represented by the above formulas is bonded to the (poly) ethylene glycol moiety (— (O—CH 2 CH 2 ) n—, where n is as defined above) in the general formula (a) The right side is bonded to the six-membered ring. For example, when A is a carbamate or α-alkoxyamide, oxygen in the above formula is bonded to the (poly) ethylene glycol moiety and nitrogen is bonded to the six-membered ring.
In the general formula (a), A is preferably the following formula:
本発明化合物(I)及びその医薬上許容される塩は、投与目的等に応じ、そのままで、あるいは各種の製剤形態で使用することができる。本発明の医薬は、通常、本発明化合物(I)又はその医薬上許容される塩、及び医薬上許容される担体を含む医薬組成物として提供される。 The present invention also includes a medicament comprising the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof.
The compound (I) of the present invention and pharmaceutically acceptable salts thereof can be used as they are or in various preparation forms depending on the purpose of administration and the like. The medicament of the present invention is usually provided as a pharmaceutical composition comprising the compound (I) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルクが挙げられる。
コーティング剤としては、例えば、ゼラチン、白糖が挙げられる。 Examples of the fluidizing agent include light anhydrous silicic acid and magnesium stearate.
Examples of the lubricant include magnesium stearate, calcium stearate, and talc.
Examples of the coating agent include gelatin and sucrose.
溶解補助剤としては、例えば、プロピレングリコール、D-マンニトール、安息香酸ベンジル、エタノール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム、ポリソルベート80が挙げられる。 Examples of the solvent include purified water, distilled water for injection, physiological saline, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.
Examples of the solubilizer include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and polysorbate 80.
等張化剤としては、例えば、塩化ナトリウム、塩化カリウム、グリセリン、マンニトール、ソルビトール、ホウ酸、ホウ砂、ブドウ糖、プロピレングリコールが挙げられる。 Examples of the stabilizer include sodium edetate, sodium bisulfite, sodium thiosulfate, sodium citrate, ascorbic acid, and dibutylhydroxytoluene.
Examples of the isotonic agent include sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, and propylene glycol.
増粘剤としては、例えば、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、ポリエチレングリコールが挙げられる。 Examples of the buffer include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, boric acid, and borax.
Examples of the thickener include hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene glycol.
無痛化剤としては、例えば、ベンジルアルコールが挙げられる。
保存剤としては、例えば、塩化ベンザルコニウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、クロロブタノール、ベンジルアルコール、デヒドロ酢酸ナトリウム、ソルビン酸が挙げられる。 Examples of the pH adjuster include hydrochloric acid, citric acid, sodium hydroxide, phosphoric acid, acetic acid, and boric acid.
Examples of soothing agents include benzyl alcohol.
Examples of the preservative include benzalkonium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.
着色剤としては、例えば、食用色素(例えば、食用赤色2号又は3号)、β-カロテンが挙げられる。
甘味剤としては、例えば、サッカリンナトリウム、グリチルリチン酸二カリウム、アスパルテームが挙げられる。 Examples of the antioxidant include sodium sulfite and ascorbic acid.
Examples of the colorant include food coloring (for example, food red No. 2 or 3) and β-carotene.
Examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, and aspartame.
以下に示す製法に記載はなくとも、必要に応じて官能基に保護基を導入し、後工程で脱保護を行う;官能基を前駆体として各工程に処し、適当な段階で所望の官能基に変換する;各製法及び工程の順序を入れ替えるなどの工夫により効率よい製造を実施することもできる。
また、各工程又は反応において、反応後の処理は、通常行われる方法で行うことができる。各工程又は反応で得られた化合物は、反応液の状態又は粗生成物として次の反応に用いることができる。生成物を、常法に従って反応混合物から単離することもできる。生成物の単離又は精製は、必要に応じて結晶化、再結晶、蒸留、分液、クロマトグラフィー等の慣用される方法を適宜選択し、また組み合わせて行うことができる。 Next, the manufacturing method of this invention compound (I) is demonstrated. The manufacturing method shown below is an example of the manufacturing method of this invention compound (I), However, The manufacturing method of the compound of this invention is not limited to these.
Although there is no description in the production method shown below, a protective group is introduced into a functional group as necessary, and deprotection is performed in a post-process; the functional group is treated as a precursor in each step, and a desired functional group is obtained at an appropriate stage. Efficient production can also be carried out by devising such as changing the order of each production method and process.
Moreover, in each process or reaction, the process after reaction can be performed by the method performed normally. The compound obtained by each process or reaction can be used for the next reaction as a reaction liquid state or a crude product. The product can also be isolated from the reaction mixture according to conventional methods. Isolation or purification of the product can be performed by appropriately selecting and combining conventional methods such as crystallization, recrystallization, distillation, liquid separation, and chromatography, as necessary.
反応時間は、用いる試薬又は溶媒により異なるが、通常1時間~24時間、好ましくは2時間~4時間である。反応温度は、用いる試薬又は溶媒により異なるが、通常25℃~160℃、好ましくは60℃~100℃である。 This reaction is preferably performed in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, and examples thereof include N, N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, ethyl acetate and the like. Preferably, N, N-dimethylformamide or acetonitrile can be mentioned.
While the reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 2 hr to 4 hr. While the reaction temperature varies depending on the reagent or solvent to be used, it is generally 25 ° C. to 160 ° C., preferably 60 ° C. to 100 ° C.
p-トルエンスルホニルクロリドは、化合物(V-1)に対して通常1~2.2当量、好ましくは1.2~1.5当量用いられる。塩基は、化合物(V-1)に対して、通常1~5当量、好ましくは1.5~3当量用いられる。かかる塩基としては、例えば、ピリジン、トリエチルアミン、N,N-ジイソプロピルエチルアミン、4-ジメチルアミノピリジン等が挙げられ、好ましくはトリエチルアミンを挙げることができる。溶媒としては反応に悪影響を及ぼさない限り特に限定されず、例えば、ジクロロメタン、クロロホルム、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン等が挙げられ、好ましくはジクロロメタンを挙げることができる。反応時間は、用いる試薬又は溶媒により異なるが、通常1時間~24時間、好ましくは14時間~21時間である。反応温度は、用いる試薬又は溶媒により異なるが、通常0℃~100℃、好ましくは25℃~50℃である。 In Step G, first, compound (V-1) is reacted with p-toluenesulfonyl chloride in the presence of a base in a normal solvent to give a compound represented by general formula (V-4) (hereinafter referred to as “compound (V— 4) "). Next, compound (V-4) is reacted with compound (IV-3) in the presence of a base in a normal solvent to produce compound (II-4).
p-Toluenesulfonyl chloride is generally used in 1 to 2.2 equivalents, preferably 1.2 to 1.5 equivalents, relative to compound (V-1). The base is generally used in 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to compound (V-1). Examples of such a base include pyridine, triethylamine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, and preferably triethylamine. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and preferably dichloromethane. While the reaction time varies depending on the reagent or solvent to be used, it is generally 1 hr to 24 hr, preferably 14 hr to 21 hr. While the reaction temperature varies depending on the reagent or solvent to be used, it is generally 0 ° C. to 100 ° C., preferably 25 ° C. to 50 ° C.
反応式4の方法では、通常溶媒中で、式(VII-1)で表される化合物(以下、「化合物(VII-1)」という)をオキサリルクロリドと反応させて式(VII-2)で表される酸クロリド(以下、「酸クロリド(VII-2)」という)とし、次いでこれをメチルアミンと反応させることにより、式(VII-3)で表されるアミド体(以下、「アミド体(VII-3)」という)を得ることができる。式(VII-3)で表されるアミド体を、水素化ホウ素ナトリウムで還元することにより、式(VII-4)で表されるチオール体(以下、「チオール体(VII-4)」という)を得ることができる。 In the formula, Me represents methyl.
In the method of reaction formula 4, a compound represented by formula (VII-1) (hereinafter referred to as “compound (VII-1)”) is reacted with oxalyl chloride in a usual solvent to obtain a compound represented by formula (VII-2). An acid chloride represented by the formula (VII-3) by reacting with an acid chloride (hereinafter referred to as “acid chloride (VII-2)”) and then reacting with methylamine. (VII-3) ”). A thiol compound represented by the formula (VII-4) (hereinafter referred to as “thiol compound (VII-4)”) is obtained by reducing the amide compound represented by the formula (VII-3) with sodium borohydride. Can be obtained.
工程Hでは、式(VI-2)で表される化合物(以下、「化合物(VI-2)」という)から式(V-5)で表される化合物(以下、「化合物(V-5)」という)を製造する。まず、化合物(VI-2)と、塩基存在下、tert-ブチルジメチルクロロシランを溶媒中で反応させる(第一工程)。次いで、溶媒中で得られた生成物と、フタルイミド、トリフェニルホスフィン、及びジエチルアゾジカルボキシラートを反応させる(第二工程)。さらに得られた生成物とヒドラジン一水和物、次いで塩酸と反応させることにより化合物(V-5)を得ることができる(第三工程)。 In the formula, Ts represents a p-toluenesulfonyl group (tosyl group), and Me represents methyl.
In step H, a compound represented by formula (V-5) is converted from a compound represented by formula (VI-2) (hereinafter referred to as “compound (VI-2)”) (hereinafter referred to as “compound (V-5)”). "). First, compound (VI-2) is reacted with tert-butyldimethylchlorosilane in a solvent in the presence of a base (first step). Next, the product obtained in the solvent is reacted with phthalimide, triphenylphosphine, and diethylazodicarboxylate (second step). Further, compound (V-5) can be obtained by reacting the resulting product with hydrazine monohydrate and then with hydrochloric acid (third step).
5-[(トリメチルシリル)エチニル]ピリジン-3-アミンの製造 Reference example 1
Preparation of 5-[(trimethylsilyl) ethynyl] pyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.10 (1H, d, J = 1.6 Hz), 8.01 (1H, d, J = 2.8 Hz), 7.03 (1H, dd, J = 2.8, 1.6 Hz), 3.68 (2H, br s), 0.25 (9H, s). To a solution of 3-amino-5-bromopyridine (3.46 g, 20 mmol), PdCl 2 (PPh 3 ) 2 (561.5 mg, 0.80 mmol), and CuI (76.2 mg, 0.40 mmol) in tetrahydrofuran (5 mL) in triethylamine ( 20 mL) and trimethylsilylacetylene (3.32 mL, 24 mmol) were added at room temperature and stirred for 5 minutes, and then stirred for 21 hours under heating to reflux. After the obtained solution was filtered, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 50/50 → 0/100) to give the title compound (2.36 g, 62%) as a brown powder.
1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (1H, d, J = 1.6 Hz), 8.01 (1H, d, J = 2.8 Hz), 7.03 (1H, dd, J = 2.8, 1.6 Hz), 3.68 (2H, br s), 0.25 (9H, s).
5-[(トリメチルシリル)エチニル]ピリジン-2-アミンの製造 Reference example 2
Preparation of 5-[(trimethylsilyl) ethynyl] pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.21 (1H, d, J = 2.0 Hz), 7.49 (1H, dd, J = 8.4, 2.0 Hz), 6.41 (1H, br d, J = 8.4 Hz), 4.56 (2H, br s), 0.24 (9H, s). 2-Amino-5-bromopyridine (5.2 g, 30 mmol), PdCl 2 (PPh 3 ) 2 (842.3 mg, 1.2 mmol), CuI (114.3 mg, 0.60 mmol), tetrahydrofuran (15 mL), triethylamine (30 mL ) And trimethylsilylacetylene (4.98 mL, 36 mmol) as raw materials and the same operation as in Reference Example 1 gave the title compound (5.17 g, 91%) as a yellow powder.
1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (1H, d, J = 2.0 Hz), 7.49 (1H, dd, J = 8.4, 2.0 Hz), 6.41 (1H, br d, J = 8.4 Hz), 4.56 (2H, br s), 0.24 (9H, s).
6-[(トリメチルシリル)エチニル]ピリジン-3-アミンの製造 Reference example 3
Preparation of 6-[(trimethylsilyl) ethynyl] pyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J = 2.8 Hz), 7.25 (1H, d, J = 8.4 Hz), 6.88 (1H, dd, J = 8.4, 2.8 Hz), 3.84 (2H, br s), 0.24 (9H, s). 3-Amino-6-bromopyridine (6.50 g, 37.6 mmol), PdCl 2 (PPh 3 ) 2 (1.05 g, 1.5 mmol), CuI (142.8 mg, 0.75 mmol), tetrahydrofuran (19 mL), triethylamine (38 mL ) And trimethylsilylacetylene (6.24 mL, 45.1 mmol) as raw materials and the same operation as in Reference Example 1 gave the title compound (6.28 g, 88%) as a brown powder.
1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (1H, d, J = 2.8 Hz), 7.25 (1H, d, J = 8.4 Hz), 6.88 (1H, dd, J = 8.4, 2.8 Hz), 3.84 (2H, br s), 0.24 (9H, s).
5-エチニルピリジン-3-アミンの製造 Reference example 4
Production of 5-ethynylpyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.13 (1H, d, J = 1.6 Hz), 8.05 (1H, d, J = 2.4 Hz), 7.05 (1H, dd, J = 2.4, 1.6 Hz), 3.72 (2H, br s), 3.14 (1H, s). To a solution of 5-[(trimethylsilyl) ethynyl] pyridin-3-amine (1.90 g, 10 mmol) in tetrahydrofuran (10 mL) was added a solution of sodium hydroxide (1.00 g) in methanol (10 mL) at room temperature for 4 hours. Stir. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 50/50 → 25/75) to give the title compound (800.1 mg, 68%) as a brown powder.
1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (1H, d, J = 1.6 Hz), 8.05 (1H, d, J = 2.4 Hz), 7.05 (1H, dd, J = 2.4, 1.6 Hz), 3.72 (2H, br s), 3.14 (1H, s).
5-エチニルピリジン-2-アミンの製造 Reference Example 5
Production of 5-ethynylpyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.23 (1H, d, J = 2.0 Hz), 7.51 (1H, dd, J = 8.8, 2.0 Hz), 6.43 (1H, br d, J = 8.8 Hz), 4.59 (2H, br s), 3.05 (1H, s). Using 5-[(trimethylsilyl) ethynyl] pyridin-2-amine (4.40 g, 23.2 mmol), tetrahydrofuran (23 mL), sodium hydroxide (2.30 g), and methanol (23 mL) as raw materials, The same operation was performed to obtain the title compound (2.71 g, 99%) as a brown powder.
1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (1H, d, J = 2.0 Hz), 7.51 (1H, dd, J = 8.8, 2.0 Hz), 6.43 (1H, br d, J = 8.8 Hz), 4.59 (2H, br s), 3.05 (1H, s).
6-エチニルピリジン-3-アミンの製造 Reference Example 6
Preparation of 6-ethynylpyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J = 2.8 Hz), 7.27 (1H, d, J = 8.4 Hz), 6.89 (1H, dd, J = 8.4, 2.8 Hz), 3.89 (2H, br s), 3.01 (1H, s). 6-[(Trimethylsilyl) ethynyl] pyridin-3-amine (6.28 g, 33.0 mmol), tetrahydrofuran (33 mL), sodium hydroxide (3.30 g), and methanol (33 mL) were used as raw materials. The same operation was performed to obtain the title compound (3.60 g, 92%) as a black powder.
1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (1H, d, J = 2.8 Hz), 7.27 (1H, d, J = 8.4 Hz), 6.89 (1H, dd, J = 8.4, 2.8 Hz), 3.89 (2H, br s), 3.01 (1H, s).
2-(2-メトキシエトキシ)エタン-1-アミンの製造 Reference Example 7
Preparation of 2- (2-methoxyethoxy) ethan-1-amine
1H NMR (400 MHz, CDCl3) δ 3.64-3.61 (2H, m), 3.57-3.55 (2H, m), 3.51 (2H, t, J = 5.2 Hz), 3.39 (3H, s), 2.89-2.87 (2H, m). Diethylene glycol monomethyl ether (3.9 mL, 33.3 mmol) and diethyl azodicarboxylate (2.2 mol / L toluene) were added to a solution of phthalimide (4.90 g, 34.2 mmol) and triphenylphosphine (9.00 g, 34.2 mmol) in tetrahydrofuran (180 mL). (Solution) (15.5 mL, 34.1 mmol) was added at room temperature and stirred overnight. Ethanol (60 mL) was further added to the obtained solution, and the mixture was stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. Ethyl acetate (50 mL) and hexane (50 mL) were added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, ethanol (120 mL) and hydrazine monohydrate (2.4 mL, 68.6 mmol) were added, and the mixture was stirred overnight with heating under reflux. The solution was cooled to room temperature, concentrated hydrochloric acid (15 mL) was added, and the mixture was stirred with heating under reflux for 1 hr. The solution was cooled to room temperature, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue and washed with diethyl ether. The aqueous layer was adjusted to pH = 13 with 3N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound (1.74 g, 44%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 3.64-3.61 (2H, m), 3.57-3.55 (2H, m), 3.51 (2H, t, J = 5.2 Hz), 3.39 (3H, s), 2.89- 2.87 (2H, m).
2-[2-(2-メトキシエトキシ)エトキシ]エタン-1-アミンの製造 Reference Example 8
Preparation of 2- [2- (2-methoxyethoxy) ethoxy] ethan-1-amine
1H NMR (400 MHz, CDCl3) δ 3.67-3.64 (6H, m), 3.57-3.55 (2H, m), 3.51 (2H, t, J = 5.2 Hz), 3.38 (3H, s), 2.87 (2H, br t, J = 5.2 Hz). Phthalimide (5.59 g, 38 mmol), triphenylphosphine (10.3 g, 39.2 mmol), triethylene glycol monomethyl ether (6 mL, 38.4 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution) (18.2 mL, 40 mmol), tetrahydrofuran (150 mL), ethanol (220 mL), and hydrazine monohydrate (3 mL, 84.5 mmol) were used as starting materials and the same procedure as in Reference Example 7 was performed to give the title compound (4.48 g, 72%) was obtained as a yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 3.67-3.64 (6H, m), 3.57-3.55 (2H, m), 3.51 (2H, t, J = 5.2 Hz), 3.38 (3H, s), 2.87 ( 2H, br t, J = 5.2 Hz).
2,5,8,11-テトラオキサトリデカン-13-アミンの製造 Reference Example 9
Preparation of 2,5,8,11-tetraoxatridecane-13-amine
1H NMR (400 MHz, CDCl3) δ 3.67-3.62 (10H, m), 3.56-3.54 (2H, m), 3.51-3.49 (2H, m), 3.37 (3H, s), 2.88-2.83 (2H, m). Phthalimide (2.28 g, 15.5 mmol), triphenylphosphine (4.06 g, 15.5 mmol), tetraethylene glycol monomethyl ether (3 mL, 15 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution) (7.2 mL, 15.9 mmol), tetrahydrofuran (60 mL), ethanol (50 mL), and hydrazine monohydrate (1.2 mL, 33 mmol) were used as starting materials and the same procedure as in Reference Example 7 was performed to give the title compound (2.94 g, 95%) as a yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 3.67-3.62 (10H, m), 3.56-3.54 (2H, m), 3.51-3.49 (2H, m), 3.37 (3H, s), 2.88-2.83 (2H , m).
2,5,8,11,14-ペンタオキサヘキサデカン-16-アミンの製造 Reference Example 10
Preparation of 2,5,8,11,14-pentaoxahexadecane-16-amine
1H NMR (400 MHz, CDCl3) δ 3.66-3.64 (14H, m), 3.56-3.54 (2H, m), 3.51 (2H, d, J = 5.2 Hz), 3.38 (3H, s), 2.86 (2H, t, J = 5.2 Hz). Phthalimide (1.34 g, 9.4 mmol), triphenylphosphine (2.47 g, 9.4 mmol), pentaethylene glycol monomethyl ether (2 mL, 8.6 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution) (4.3 mL, 9.4 mmol), tetrahydrofuran (50 mL), ethanol (100 mL), and hydrazine monohydrate (660 μL, 18.8 mmol) were used as starting materials and the same procedure as in Reference Example 7 was performed to give the title compound (1.34 g, 62%) was obtained as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 3.66-3.64 (14H, m), 3.56-3.54 (2H, m), 3.51 (2H, d, J = 5.2 Hz), 3.38 (3H, s), 2.86 ( (2H, t, J = 5.2 Hz).
1-(3-エチニルフェニル)-3-(2-メトキシエチル)ウレアの製造 Reference Example 11
Production of 1- (3-ethynylphenyl) -3- (2-methoxyethyl) urea
1H NMR (400 MHz, CDCl3) δ 7.42 (1H, br s), 7.37 (1H, br d, J = 7.6 Hz), 7.23 (1H, t, J = 7.6 Hz), 7.17 (1H, br d, J = 7.6 Hz), 7.03 (1H, br s), 5.31 (1H, br s), 3.52 (2H, br t, J = 4.8 Hz), 3.46-3.42 (2H, m), 3.38 (3H, s), 3.04 (1H, s). 3-Ethynylaniline (585.8 mg, 5.0 mmol) and pyridine (0.44 mL, 5.5 mmol) were added to a solution of 4-nitrophenyl chloroformate (1.00 g, 5.0 mmol) in dichloromethane (50 mL), and the mixture was stirred overnight at room temperature. . To the obtained solution was further added 2-methoxyethylamine (0.94 mL, 11 mmol), and the mixture was stirred at room temperature for 5 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 50/50 → 0/100) to give the title compound (1.05 g, 96%) as a white powder.
1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (1H, br s), 7.37 (1H, br d, J = 7.6 Hz), 7.23 (1H, t, J = 7.6 Hz), 7.17 (1H, br d , J = 7.6 Hz), 7.03 (1H, br s), 5.31 (1H, br s), 3.52 (2H, br t, J = 4.8 Hz), 3.46-3.42 (2H, m), 3.38 (3H, s ), 3.04 (1H, s).
1-(3-エチニルフェニル)-3-[2-(2-メトキシエトキシ)エチル]ウレアの製造 Reference Example 12
Preparation of 1- (3-ethynylphenyl) -3- [2- (2-methoxyethoxy) ethyl] urea
1H NMR (400 MHz, CDCl3) δ 7.45-7.44 (1H, m), 7.42 (1H, br d, J = 7.6 Hz), 7.23 (1H, t, J = 7.6 Hz), 7.15 (1H, br dt, J = 7.6, 1.2 Hz), 6.98 (1H, br s), 5.31 (1H, br s), 3.67-3.65 (2H, m), 3.62 (2H, br t, J = 4.8 Hz), 3.58-3.56 (2H, m), 3.47-3.43 (2H, m), 3.38 (3H, s), 3.04 (1H, s). 4-nitrophenyl chloroformate (907.0 mg, 4.5 mmol), dichloromethane (45 mL), 3-ethynylaniline (527.1 mg, 4.5 mmol), pyridine (0.58 mL, 7.2 mmol), and 2- (2-methoxyethoxy ) Ethan-1-amine (1.43 g, 12 mmol) was used as a starting material and was treated in the same manner as in Reference Example 11 to obtain the title compound (620.0 mg, 53%) as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.45-7.44 (1H, m), 7.42 (1H, br d, J = 7.6 Hz), 7.23 (1H, t, J = 7.6 Hz), 7.15 (1H, br dt, J = 7.6, 1.2 Hz), 6.98 (1H, br s), 5.31 (1H, br s), 3.67-3.65 (2H, m), 3.62 (2H, br t, J = 4.8 Hz), 3.58- 3.56 (2H, m), 3.47-3.43 (2H, m), 3.38 (3H, s), 3.04 (1H, s).
1-(3-エチニルフェニル)-3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレアの製造 Reference Example 13
Preparation of 1- (3-ethynylphenyl) -3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} urea
1H NMR (400 MHz, CDCl3) δ 7.58 (1H, br s), 7.51 (1H, br d, J = 7.6 Hz), 7.48 (1H, t, J = 1.2 Hz), 7.21 (1H, t, J = 7.6 Hz), 7.10 (1H, br dt, J = 7.6, 1.2 Hz), 5.82 (1H, br s), 3.70-3.67 (6H, m), 3.64-3.61 (4H, m), 3.47-3.43 (5H, m), 3.02 (1H, s). 4-nitrophenyl chloroformate (907.0 mg, 4.5 mmol), dichloromethane (45 mL), 3-ethynylaniline (527.1 mg, 4.5 mmol), pyridine (0.58 mL, 7.2 mmol), and 2- [2- (2 -Methoxyethoxy) ethoxy] ethane-1-amine (1.96 g, 12 mmol) was used as a starting material and was treated in the same manner as in Reference Example 11 to obtain the title compound (819.5 mg, 59%) as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (1H, br s), 7.51 (1H, br d, J = 7.6 Hz), 7.48 (1H, t, J = 1.2 Hz), 7.21 (1H, t, J = 7.6 Hz), 7.10 (1H, br dt, J = 7.6, 1.2 Hz), 5.82 (1H, br s), 3.70-3.67 (6H, m), 3.64-3.61 (4H, m), 3.47-3.43 (5H, m), 3.02 (1H, s).
1-(3-エチニルフェニル)-3-(2,5,8,11-テトラオキサトリデカン-13-イル)ウレアの製造 Reference Example 14
Preparation of 1- (3-ethynylphenyl) -3- (2,5,8,11-tetraoxatridecan-13-yl) urea
1H NMR (400 MHz, CDCl3) δ 7.73 (1H, br s), 7.54-7.52 (2H, m), 7.19 (1H, br t, J = 7.1 Hz), 7.09 (1H, br d, J = 7.1 Hz), 5.95 (1H, br s), 3.74-3.72 (4H, m), 3.68-3.65 (4H, m), 3.62-3.58 (6H, m), 3.45-3.41 (2H, m), 3.32 (3H, s), 3.01 (1H, s). 4-nitrophenyl chloroformate (516.0 mg, 2.6 mmol), dichloromethane (25 mL), 3-ethynylaniline (288 μL, 2.6 mmol), pyridine (228 μL, 2.8 mmol), and 2,5,8,11 The title compound (393.0 mg, 44%) was obtained as a pale yellow oil in the same manner as in Reference Example 11 using -tetraoxatridecan-13-amine (884.5 mg, 4.3 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (1H, br s), 7.54-7.52 (2H, m), 7.19 (1H, br t, J = 7.1 Hz), 7.09 (1H, br d, J = 7.1 Hz), 5.95 (1H, br s), 3.74-3.72 (4H, m), 3.68-3.65 (4H, m), 3.62-3.58 (6H, m), 3.45-3.41 (2H, m), 3.32 ( 3H, s), 3.01 (1H, s).
1-(3-エチニルフェニル)-3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレアの製造 Reference Example 15
Preparation of 1- (3-ethynylphenyl) -3- (2,5,8,11,14-pentaoxahexadecan-16-yl) urea
1H NMR (400 MHz, CDCl3) δ 7.80 (1H, br s), 7.55 (1H, s), 7.54 (1H, d, J = 7.7 Hz), 7.19 (1H, br t, J = 7.7 Hz), 7.08 (1H, br d, J = 7.7 Hz), 6.05 (1H, br s), 3.75-3.72 (4H, m), 3.70-3.64 (6H, m), 3.62-3.59 (6H, m), 3.48-3.43 (4H, m), 3.28 (3H, s), 3.01 (1H, s). 4-nitrophenyl chloroformate (516.0 mg, 2.6 mmol), dichloromethane (25 mL), 3-ethynylaniline (288 μL, 2.6 mmol), pyridine (228 μL, 2.8 mmol), and 2,5,8,11 , 14-Pentaoxahexadecan-16-amine (1.00 g, 4.3 mmol) was used in the same manner as in Reference Example 11 to give the title compound (965.0 mg, 96%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (1H, br s), 7.55 (1H, s), 7.54 (1H, d, J = 7.7 Hz), 7.19 (1H, br t, J = 7.7 Hz) , 7.08 (1H, br d, J = 7.7 Hz), 6.05 (1H, br s), 3.75-3.72 (4H, m), 3.70-3.64 (6H, m), 3.62-3.59 (6H, m), 3.48 -3.43 (4H, m), 3.28 (3H, s), 3.01 (1H, s).
1-(5-エチニルピリジン-3-イル)-3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレアの製造 Reference Example 16
Preparation of 1- (5-ethynylpyridin-3-yl) -3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} urea
1H NMR (400 MHz, CDCl3) δ 8.40 (1H, d, J = 2.8 Hz), 8.30 (1H, d, J = 2.0 Hz), 8.22 (1H, br dd, J = 2.8, 2.0 Hz), 7.96 (1H, br s), 6.01 (1H, br s), 3.72-3.62 (10H, m), 3.46-3.43 (5H, m), 3.15 (1H, s). 5-Ethynylpyridin-3-amine (236.3 mg, 2.0 mmol) was added to a solution of 4-nitrophenyl chloroformate (403.1 mg, 2.0 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 1 hour and then under reduced pressure. The solvent was distilled off. To a 1,4-dioxane (20 mL) solution of the obtained crude product, 2- [2- (2-methoxyethoxy) ethoxy] ethan-1-amine (359.1 mg, 2.2 mmol) and triethylamine (0.62 mL, 4.4 mmol) was added, and the mixture was stirred overnight under reflux with heating, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 91/9) to give the title compound (447.7 mg, 73%) as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (1H, d, J = 2.8 Hz), 8.30 (1H, d, J = 2.0 Hz), 8.22 (1H, br dd, J = 2.8, 2.0 Hz), 7.96 (1H, br s), 6.01 (1H, br s), 3.72-3.62 (10H, m), 3.46-3.43 (5H, m), 3.15 (1H, s).
1-(5-エチニルピリジン-3-イル)-3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレアの製造 Reference Example 17
Preparation of 1- (5-ethynylpyridin-3-yl) -3- (2,5,8,11,14-pentaoxahexadecan-16-yl) urea
1H NMR (400 MHz, CDCl3) δ 8.48 (1H, d, J = 2.8 Hz), 8.29 (1H, d, J = 1.6 Hz), 8.23 (1H, br dd, J = 2.8, 1.6 Hz), 8.06 (1H, br s), 6.02 (1H, br s), 3.78-3.75 (4H, m), 3.72-3.59 (12H, m), 3.45-3.43 (4H, m), 3.27 (s, 3H), 3.14 (1H, s). 4-nitrophenyl chloroformate (201.6 mg, 1.0 mmol), tetrahydrofuran (10 mL), 5-ethynylpyridin-3-amine (118.2 mg, 1.0 mmol), 1,4-dioxane (10 mL), 2,5 , 8,11,14-pentaoxahexadecane-16-amine (276.5 mg, 1.1 mmol) and triethylamine (0.31 mL, 2.2 mmol) were used as starting materials in the same manner as in Reference Example 16 to give the title compound (249.5 mg, 63%) was obtained as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (1H, d, J = 2.8 Hz), 8.29 (1H, d, J = 1.6 Hz), 8.23 (1H, br dd, J = 2.8, 1.6 Hz), 8.06 (1H, br s), 6.02 (1H, br s), 3.78-3.75 (4H, m), 3.72-3.59 (12H, m), 3.45-3.43 (4H, m), 3.27 (s, 3H), 3.14 (1H, s).
1-(4-エチニルフェニル)-3-(2-メトキシエチル)ウレアの製造 Reference Example 18
Production of 1- (4-ethynylphenyl) -3- (2-methoxyethyl) urea
1H NMR (400 MHz, CDCl3) δ 7.41 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.14 (1H, br s), 5.31 (1H, br s), 3.52 (2H, br t, J = 4.8 Hz), 3.46-3.42 (2H, m), 3.39 (3H, s), 3.02 (1H, s). To a solution of 4-nitrophenyl chloroformate (873.4 mg, 4.3 mmol) in dichloromethane (30 mL), add pyridine (0.42 mL, 5.2 mmol) and 4-ethynylaniline (502.3 mg, 4.3 mmol), and stir at room temperature for 45 minutes. did. To this solution was added 2-methoxyethylamine (664.4 mg, 8.8 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour, diluted with dichloromethane, and washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 1/2) to give the title compound (759.7 mg, 81%) as a pale orange solid.
1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.14 (1H, br s), 5.31 (1H, br s) , 3.52 (2H, br t, J = 4.8 Hz), 3.46-3.42 (2H, m), 3.39 (3H, s), 3.02 (1H, s).
1-(4-エチニルフェニル)-3-[2-(2-メトキシエトキシ)エチル]ウレアの製造 Reference Example 19
Preparation of 1- (4-ethynylphenyl) -3- [2- (2-methoxyethoxy) ethyl] urea
1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (5H, m), 5.54 (1H, br s), 3.65-3.64 (2H, m), 3.61 (2H, t, J = 5.2 Hz), 3.57-3.54 (2H, m), 3.46-3.42 (2H, m), 3.37 (3H, s), 3.00 (1H, s). 4-nitrophenyl chloroformate (622.2 mg, 3.1 mmol), dichloromethane (12 mL), pyridine (0.25 mL, 3.1 mmol), 4-ethynylaniline (300 mg, 2.6 mmol), and 2- (2-methoxyethoxy) ) Ethan-1-amine (613.2 mg, 5.1 mmol) was used as a starting material and was treated in the same manner as in Reference Example 18 to obtain the title compound (485.3 mg, 72%) as an orange oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.31 (5H, m), 5.54 (1H, br s), 3.65-3.64 (2H, m), 3.61 (2H, t, J = 5.2 Hz), 3.57 -3.54 (2H, m), 3.46-3.42 (2H, m), 3.37 (3H, s), 3.00 (1H, s).
1-(4-エチニルフェニル)-3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレアの製造 Reference Example 20
Preparation of 1- (4-ethynylphenyl) -3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} urea
1H NMR (400 MHz, CDCl3) δ 7.73 (1H, br s), 7.38 (4H, m), 5.87 (1H, br s), 3.69 (6H, br m), 3.63-3.61 (4H, m), 3.46-3.45 (5H, m), 2.99 (1H, s). 4-nitrophenyl chloroformate (3.43 g, 17.0 mmol), dichloromethane (130 mL), pyridine (1.54 mL, 19.0 mmol), 4-ethynylaniline (2.0 g, 17.0 mmol), and 2- [2- (2 -Methoxyethoxy) ethoxy] ethan-1-amine (3.60 g, 22.1 mmol) was used as a starting material and was treated in the same manner as in Reference Example 18 to obtain the title compound (3.87 g, 74%) as an orange oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (1H, br s), 7.38 (4H, m), 5.87 (1H, br s), 3.69 (6H, br m), 3.63-3.61 (4H, m) , 3.46-3.45 (5H, m), 2.99 (1H, s).
1-(4-エチニルフェニル)-3-(2,5,8,11-テトラオキサトリデカン-13-イル)ウレアの製造 Reference Example 21
Preparation of 1- (4-ethynylphenyl) -3- (2,5,8,11-tetraoxatridecan-13-yl) urea
1H NMR (400 MHz, CDCl3) δ 7.82 (1H, br s), 7.43 (2H, br d, J = 8.8 Hz), 7.37 (2H, br d, J = 8.8 Hz), 5.90 (1H, br t, J = 5.2 Hz), 3.77-3.74 (4H, m), 3.68-3.65 (4H, m), 3.63-3.58 (6H, m), 3.45-3.41 (2H, m), 3.30 (3H, s,), 2.99 (1H, s). 4-nitrophenyl chloroformate (253.9 mg, 1.3 mmol), dichloromethane (4 mL), pyridine (0.12 mL, 1.5 mmol), 4-ethynylaniline (120.5 mg, 1.0 mmol), and 2,5,8,11 The title compound (348.5 mg, 97%) was obtained as an orange oil by operating in the same manner as in Reference Example 18 using 4-tetraoxatridecan-13-amine (417.9 mg, 2.0 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (1H, br s), 7.43 (2H, br d, J = 8.8 Hz), 7.37 (2H, br d, J = 8.8 Hz), 5.90 (1H, br t, J = 5.2 Hz), 3.77-3.74 (4H, m), 3.68-3.65 (4H, m), 3.63-3.58 (6H, m), 3.45-3.41 (2H, m), 3.30 (3H, s, ), 2.99 (1H, s).
1-(4-エチニルフェニル)-3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレアの製造 Reference Example 22
Production of 1- (4-ethynylphenyl) -3- (2,5,8,11,14-pentaoxahexadecan-16-yl) urea
1H NMR (400 MHz, CDCl3) δ 7.93 (1H, br s), 7.44 (2H, br d, J = 8.8 Hz), 7.38 (2H, br d, J = 8.8 Hz), 5.99 (1H, br t, J = 4.4 Hz), 3.78-3.73 (4H, m), 3.71-3.68 (2H, m), 3.67-3.64 (4H, m), 3.63-3.58 (6H, m), 3.45-3.41 (4H, m), 3.27 (3H, s), 2.98 (1H, s). 4-nitrophenyl chloroformate (216.0 mg, 1.1 mmol), dichloromethane (4 mL), pyridine (0.10 mL, 1.2 mmol), 4-ethynylaniline (103.5 mg, 0.88 mmol), and 2,5,8,11 , 14-pentaoxahexadecan-16-amine (431.5 mg, 1.7 mmol) was used as a starting material and was treated in the same manner as in Reference Example 18 to obtain the title compound (335.2 mg, 96%) as an orange oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (1H, br s), 7.44 (2H, br d, J = 8.8 Hz), 7.38 (2H, br d, J = 8.8 Hz), 5.99 (1H, br t, J = 4.4 Hz), 3.78-3.73 (4H, m), 3.71-3.68 (2H, m), 3.67-3.64 (4H, m), 3.63-3.58 (6H, m), 3.45-3.41 (4H, m), 3.27 (3H, s), 2.98 (1H, s).
1-(5-エチニルピリジン-2-イル)-3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレアの製造 Reference Example 23
Preparation of 1- (5-ethynylpyridin-2-yl) -3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} urea
1H NMR (400 MHz, CD3OD) δ 8.31 (1H, d, J = 1.8 Hz), 7.71 (1H, dd, J = 8.8, 1.8 Hz), 7.11 (1H, d, J = 8.8 Hz), 3.65-3.59 (8H, m), 3.52-3.47 (4H, m), 3.34 (4H, br s). 4-nitrophenyl chloroformate (341.0 mg, 1.7 mmol), dichloromethane (18 mL), 5-ethynylpyridin-2-amine (200.0 mg, 1.7 mmol), 1,4-dioxane (15 mL), triethylamine (1.2 mL, 8.5 mmol), and 2- [2- (2-methoxyethoxy) ethoxy] ethan-1-amine (408.0 mg, 2.5 mmol) were used as starting materials and were treated in the same manner as in Reference Example 16 to give the title compound ( 168.0 mg, 32%) was obtained as a pale yellow oil.
1 H NMR (400 MHz, CD 3 OD) δ 8.31 (1H, d, J = 1.8 Hz), 7.71 (1H, dd, J = 8.8, 1.8 Hz), 7.11 (1H, d, J = 8.8 Hz), 3.65-3.59 (8H, m), 3.52-3.47 (4H, m), 3.34 (4H, br s).
1-(5-エチニルピリジン-2-イル)-3-(2,5,8,11-テトラオキサトリデカン-13-イル)ウレアの製造 Reference Example 24
Preparation of 1- (5-ethynylpyridin-2-yl) -3- (2,5,8,11-tetraoxatridecan-13-yl) urea
1H NMR (400 MHz, CD3OD) δ 8.31 (1H, d, J = 1.8 Hz), 7.72 (1H, dd, J = 8.8, 1.8 Hz), 7.12 (1H, d, J = 8.8 Hz), 3.67-3.59 (12H, m), 3.52-3.46 (4H, m), 3.35 (1H, s), 3.34 (3H, s). 4-nitrophenyl chloroformate (341.0 mg, 1.7 mmol), dichloromethane (18 mL), 5-ethynylpyridin-2-amine (200.0 mg, 1.7 mmol), 1,4-dioxane (15 mL), triethylamine (520 μL, 1.9 mmol) and 2,5,8,11-tetraoxatridecan-13-amine (526.0 mg, 2.5 mmol) were used as the starting material and the same procedure as in Reference Example 16 was performed to give the title compound (284.0 mg , 48%) as a pale yellow oil.
1 H NMR (400 MHz, CD 3 OD) δ 8.31 (1H, d, J = 1.8 Hz), 7.72 (1H, dd, J = 8.8, 1.8 Hz), 7.12 (1H, d, J = 8.8 Hz), 3.67-3.59 (12H, m), 3.52-3.46 (4H, m), 3.35 (1H, s), 3.34 (3H, s).
1-(5-エチニルピリジン-2-イル)-3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレアの製造 Reference Example 25
Preparation of 1- (5-ethynylpyridin-2-yl) -3- (2,5,8,11,14-pentaoxahexadecan-16-yl) urea
1H NMR (400 MHz, CD3OD) δ 8.31 (1H, d, J = 1.8 Hz), 7.72 (1H, dd, J = 8.8, 1.8 Hz), 7.12 (1H, d, J = 8.8 Hz), 3.66-3.59 (16H, m), 3.53-3.46 (4H, m), 3.35 (1H, s), 3.34 (3H, s). 4-nitrophenyl chloroformate (341.0 mg, 1.7 mmol), dichloromethane (20 mL), 5-ethynylpyridin-2-amine (200.0 mg, 1.7 mmol), 1,4-dioxane (15 mL), triethylamine (260 μL, 1.9 mmol), and 2,5,8,11,14-pentaoxahexadecan-16-amine (850.0 mg, 3.4 mmol) were used as the starting material and the title compound (553.0 mg, 83%) as a yellow oil.
1 H NMR (400 MHz, CD 3 OD) δ 8.31 (1H, d, J = 1.8 Hz), 7.72 (1H, dd, J = 8.8, 1.8 Hz), 7.12 (1H, d, J = 8.8 Hz), 3.66-3.59 (16H, m), 3.53-3.46 (4H, m), 3.35 (1H, s), 3.34 (3H, s).
1-(6-エチニルピリジン-3-イル)-3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレアの製造 Reference Example 26
Preparation of 1- (6-ethynylpyridin-3-yl) -3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} urea
1H NMR (400 MHz, CDCl3) δ 8.37 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 8.12 (1H, dd, J = 8.6, 2.4 Hz), 7.40 (1H, d, J = 8.6 Hz), 6.17 (1H, br s), 3.67-3.58 (10H, m), 3.44-3.43 (2H, m), 3.40 (3H, s), 3.13 (1H, s). 4-nitrophenyl chloroformate (341.0 mg, 1.7 mmol), tetrahydrofuran (18 mL), 6-ethynylpyridin-3-amine (200.0 mg, 1.7 mmol), 1,4-dioxane (15 mL), triethylamine (260 μL, 1.9 mmol), and 2- [2- (2-methoxyethoxy) ethoxy] ethan-1-amine (552.0 mg, 3.4 mmol) were used as starting materials and were treated in the same manner as in Reference Example 16 to give the title compound ( (319.7 mg, 62%) was obtained as a pale orange oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 8.12 (1H, dd, J = 8.6, 2.4 Hz), 7.40 (1H, d, J = 8.6 Hz), 6.17 (1H, br s), 3.67-3.58 (10H, m), 3.44-3.43 (2H, m), 3.40 (3H, s), 3.13 (1H, s).
1-(6-エチニルピリジン-3-イル)-3-(2,5,8,11-テトラオキサトリデカン-13-イル)ウレアの製造 Reference Example 27
Preparation of 1- (6-ethynylpyridin-3-yl) -3- (2,5,8,11-tetraoxatridecan-13-yl) urea
1H NMR (400 MHz, CDCl3) δ 8.39 (1H, d, J = 2.4 Hz), 8.17 (1H, dd, J = 8.7, 2.4 Hz), 8.11 (1H, s), 7.39 (1H, d, J = 8.7 Hz), 6.13 (1H, br s), 3.76-3.74 (4H, m), 3.68-3.66 (6H, m), 3.62-3.59 (4H, m), 3.46-3.42 (2H, m), 3.31 (3H, s), 3.05 (1H, s). 4-nitrophenyl chloroformate (273.0 mg, 1.4 mmol), tetrahydrofuran (15 mL), 6-ethynylpyridin-3-amine (160.0 mg, 1.4 mmol), 1,4-dioxane (15 mL), triethylamine (260 μL, 1.9 mmol) and 2,5,8,11-tetraoxatridecan-13-amine (560.0 mg, 2.7 mmol) were used as the starting material and were treated in the same manner as in Reference Example 16 to give the title compound (417.3 mg , 88%) as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (1H, d, J = 2.4 Hz), 8.17 (1H, dd, J = 8.7, 2.4 Hz), 8.11 (1H, s), 7.39 (1H, d, J = 8.7 Hz), 6.13 (1H, br s), 3.76-3.74 (4H, m), 3.68-3.66 (6H, m), 3.62-3.59 (4H, m), 3.46-3.42 (2H, m), 3.31 (3H, s), 3.05 (1H, s).
1-(6-エチニルピリジン-3-イル)-3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレアの製造 Reference Example 28
Preparation of 1- (6-ethynylpyridin-3-yl) -3- (2,5,8,11,14-pentaoxahexadecan-16-yl) urea
1H NMR (400 MHz, CDCl3) δ 8.43 (1H, br d, J = 2.4 Hz), 8.17-8.16 (2H, m), 7.40 (1H, d, J = 8.4 Hz), 6.13 (1H, br s), 3.77-3.58 (18H, m), 3.45-3.44 (2H, m), 3.26 (3H, s), 3.06 (1H, s). 4-nitrophenyl chloroformate (341.0 mg, 1.7 mmol), tetrahydrofuran (18 mL), 6-ethynylpyridin-3-amine (200.0 mg, 1.7 mmol), 1,4-dioxane (15 mL), triethylamine (260 μL, 1.9 mmol) and 2,5,8,11,14-pentaoxahexadecan-16-amine (850.0 mg, 3.4 mmol) were used as starting materials in the same manner as in Reference Example 16, and the title compound (585.0 mg, 88%) as a yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (1H, br d, J = 2.4 Hz), 8.17-8.16 (2H, m), 7.40 (1H, d, J = 8.4 Hz), 6.13 (1H, br s), 3.77-3.58 (18H, m), 3.45-3.44 (2H, m), 3.26 (3H, s), 3.06 (1H, s).
2-メトキシエチル (3-エチニルフェニル)カルバメートの製造 Reference Example 29
Preparation of 2-methoxyethyl (3-ethynylphenyl) carbamate
1H NMR (400 MHz, CDCl3) δ 7.50 (1H, br s), 7.39 (1H, br d, J = 7.6 Hz), 7.25 (1H, br t, J = 7.6 Hz), 7.19 (1H, br d, J = 7.6 Hz), 6.74 (1H, br s), 4.33 (2H, br t, J = 4.4 Hz), 3.64 (2H, br t, J = 4.4 Hz), 3.42 (3H, s), 3.06 (1H, s). To a solution of 2-methoxyethanol (0.39 mL, 5.0 mmol) in ethyl acetate (15 mL) was added di (N-succinimidyl) carbonate (1.34 g, 5.3 mmol) and triethylamine (1.39 mL, 10 mmol) under ice-cooling. After stirring for 30 minutes, the mixture was stirred overnight at room temperature. 3-Ethynylaniline (0.62 mL, 5.5 mmol) was further added to the resulting solution, and the mixture was stirred for 5 hours under reflux with heating. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 80/20 → 50/50) to give the title compound (771.0 mg, 70%) as a colorless oil Obtained as a thing.
1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (1H, br s), 7.39 (1H, br d, J = 7.6 Hz), 7.25 (1H, br t, J = 7.6 Hz), 7.19 (1H, br d, J = 7.6 Hz), 6.74 (1H, br s), 4.33 (2H, br t, J = 4.4 Hz), 3.64 (2H, br t, J = 4.4 Hz), 3.42 (3H, s), 3.06 (1H, s).
2-(2-メトキシエトキシ)エチル (3-エチニルフェニル)カルバメートの製造 Reference Example 30
Preparation of 2- (2-methoxyethoxy) ethyl (3-ethynylphenyl) carbamate
1H NMR (400 MHz, CDCl3) δ 7.50 (1H, br s), 7.39 (1H, br d, J = 7.6 Hz), 7.25 (1H, t, J = 7.6 Hz), 7.18 (1H, br dt, J = 7.6, 1.2 Hz), 6.75 (1H, br s), 4.34 (2H, br t, J = 4.4 Hz), 3.75 (2H, br t, J = 4.4 Hz), 3.68-3.66 (2H, m), 3.58-3.56 (2H, m), 3.39 (3H, s), 3.05 (1H, s). Diethylene glycol monomethyl ether (0.59 mL, 5.0 mmol), ethyl acetate (15 mL), di (N-succinimidyl) carbonate (1.34 g, 5.3 mmol), triethylamine (1.39 mL, 10 mmol), and 3-ethynylaniline (0.62 mL) , 5.5 mmol) as a starting material, and the title compound (757.5 mg, 57%) was obtained as a colorless oil in the same manner as in Reference Example 29.
1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (1H, br s), 7.39 (1H, br d, J = 7.6 Hz), 7.25 (1H, t, J = 7.6 Hz), 7.18 (1H, br dt , J = 7.6, 1.2 Hz), 6.75 (1H, br s), 4.34 (2H, br t, J = 4.4 Hz), 3.75 (2H, br t, J = 4.4 Hz), 3.68-3.66 (2H, m ), 3.58-3.56 (2H, m), 3.39 (3H, s), 3.05 (1H, s).
2-[2-(2-メトキシエトキシ)エトキシ]エチル (3-エチニルフェニル)カルバメートの製造 Reference Example 31
Preparation of 2- [2- (2-methoxyethoxy) ethoxy] ethyl (3-ethynylphenyl) carbamate
1H NMR (400 MHz, CDCl3) δ 7.51 (1H, br s), 7.40 (1H, br d, J = 7.6 Hz), 7.25 (1H, t, J = 7.6 Hz), 7.18 (1H, br dt, J = 7.6, 1.2 Hz), 6.91 (1H, br s), 4.33 (2H, br t, J = 4.4 Hz), 3.75 (2H, br t, J = 4.4 Hz), 3.70-3.65 (6H, m), 3.57-3.55 (2H, m), 3.38 (3H, s), 3.05 (1H, s). Triethylene glycol monomethyl ether (0.78 mL, 5.0 mmol), ethyl acetate (15 mL), di (N-succinimidyl) carbonate (1.34 g, 5.3 mmol), triethylamine (1.39 mL, 10 mmol), and 3-ethynylaniline ( The title compound (1.00 g, 68%) was obtained as a pale yellow oil in the same manner as in Reference Example 29 using 0.62 mL, 5.5 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (1H, br s), 7.40 (1H, br d, J = 7.6 Hz), 7.25 (1H, t, J = 7.6 Hz), 7.18 (1H, br dt , J = 7.6, 1.2 Hz), 6.91 (1H, br s), 4.33 (2H, br t, J = 4.4 Hz), 3.75 (2H, br t, J = 4.4 Hz), 3.70-3.65 (6H, m ), 3.57-3.55 (2H, m), 3.38 (3H, s), 3.05 (1H, s).
2-メトキシエチル (4-エチニルフェニル)カルバメートの製造 Reference Example 32
Preparation of 2-methoxyethyl (4-ethynylphenyl) carbamate
1H NMR (400 MHz, CDCl3) δ 7.43 (2H, br d, J = 8.4 Hz), 7.34 (2H, br d, J = 8.4 Hz), 6.79 (1H, br s), 4.34-4.32 (2H, br t, J = 4.4 Hz), 3.65-3.62 (2H, br t, J = 4.4 Hz), 3.41 (3H, s), 3.02 (1H, s). 2-methoxyethanol (385.9 mg, 5.1 mmol), ethyl acetate (4 mL), di (N-succinimidyl) carbonate (1.35 g, 5.3 mmol), triethylamine (2.0 mL, 14 mmol), and 4-ethynylaniline (704.2 mg, 6.0 mmol) was used as a starting material, and the title compound (913.7 mg, 82%) was obtained as an orange oil in the same manner as in Reference Example 29.
1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (2H, br d, J = 8.4 Hz), 7.34 (2H, br d, J = 8.4 Hz), 6.79 (1H, br s), 4.34-4.32 (2H , br t, J = 4.4 Hz), 3.65-3.62 (2H, br t, J = 4.4 Hz), 3.41 (3H, s), 3.02 (1H, s).
2-(2-メトキシエトキシ)エチル (4-エチニルフェニル)カルバメートの製造 Reference Example 33
Preparation of 2- (2-methoxyethoxy) ethyl (4-ethynylphenyl) carbamate
1H NMR (400 MHz, CDCl3) δ 7.44 (2H, br d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 6.77 (1H, br s), 4.34 (2H, br t, J = 4.8 Hz), 3.74 (2H, br t, J = 4.8 Hz), 3.68-3.66 (2H, m), 3.58-3.56 (2H, m), 3.39 (3H, s), 3.02 (1H, s). Diethylene glycol monomethyl ether (600.6 mg, 5.0 mmol), ethyl acetate (4 mL), di (N-succinimidyl) carbonate (1.35 g, 5.3 mmol), triethylamine (2 mL, 14 mmol), and 4-ethynylaniline (709.7 mg) , 6.1 mmol) as a starting material and the same operation as in Reference Example 29 gave the title compound (1.06 g, 80%) as an orange oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.44 (2H, br d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 6.77 (1H, br s), 4.34 (2H, br t , J = 4.8 Hz), 3.74 (2H, br t, J = 4.8 Hz), 3.68-3.66 (2H, m), 3.58-3.56 (2H, m), 3.39 (3H, s), 3.02 (1H, s ).
2-[2-(2-メトキシエトキシ)エトキシ]エチル (4-エチニルフェニル)カルバメートの製造 Reference Example 34
Preparation of 2- [2- (2-methoxyethoxy) ethoxy] ethyl (4-ethynylphenyl) carbamate
1H NMR (400 MHz, CDCl3) δ 7.43 (2H, br d, J = 8.8 Hz), 7.35 (2H, br d, J = 8.8 Hz), 6.93 (1H, br s), 4.33 (2H, br t, J = 4.8 Hz), 3.74 (2H, br t, J = 4.8 Hz), 3.71-3.69 (6H, m), 3.57-3.55 (2H, m), 3.38 (3H, s), 3.02 (1H, s). Triethylene glycol monomethyl ether (824.3 mg, 5.0 mmol), ethyl acetate (4 mL), di (N-succinimidyl) carbonate (1.37 g, 5.3 mmol), triethylamine (2.0 mL, 14 mmol), and 4-ethynylaniline ( The title compound (1.21 g, 79%) was obtained as a yellow oil by the same procedure as in Reference Example 29 using 744.2 mg, 6.4 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (2H, br d, J = 8.8 Hz), 7.35 (2H, br d, J = 8.8 Hz), 6.93 (1H, br s), 4.33 (2H, br t, J = 4.8 Hz), 3.74 (2H, br t, J = 4.8 Hz), 3.71-3.69 (6H, m), 3.57-3.55 (2H, m), 3.38 (3H, s), 3.02 (1H, s).
2,5,8,11-テトラオキサトリデカン-13-イル (4-エチニルフェニル)カルバメートの製造 Reference Example 35
Preparation of 2,5,8,11-tetraoxatridecan-13-yl (4-ethynylphenyl) carbamate
1H NMR (400 MHz, CDCl3) δ 7.43 (2H, br d, J = 8.8 Hz), 7.36 (2H, br d, J = 8.8 Hz), 7.10 (1H, br s), 4.33 (2H, br t, J = 4.8 Hz), 3.74 (2H, br t, J = 4.8 Hz), 3.68-3.64 (10H, m), 3.57- 3.54 (2H, m), 3.37 (3H, s), 3.02 (1H, s). Tetraethylene glycol monomethyl ether (1.53 g, 7.4 mmol), ethyl acetate (10 mL), di (N-succinimidyl) carbonate (2.11 g, 8.2 mmol), triethylamine (3.0 mL, 22 mmol), and 4-ethynylaniline ( The title compound (1.54 g, 60%) was obtained as an orange oil in the same manner as in Reference Example 29 using 1.12 g, 9.5 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (2H, br d, J = 8.8 Hz), 7.36 (2H, br d, J = 8.8 Hz), 7.10 (1H, br s), 4.33 (2H, br t, J = 4.8 Hz), 3.74 (2H, br t, J = 4.8 Hz), 3.68-3.64 (10H, m), 3.57- 3.54 (2H, m), 3.37 (3H, s), 3.02 (1H, s).
2,5,8,11,14-ペンタオキサヘキサデカン-16-イル (4-エチニルフェニル)カルバメートの製造 Reference Example 36
Preparation of 2,5,8,11,14-pentaoxahexadecan-16-yl (4-ethynylphenyl) carbamate
1H NMR (400 MHz, CDCl3) δ 7.43 (2H, br d, J = 8.8 Hz), 7.37 (2H, br d, J = 8.8 Hz), 7.14 (1H, br s), 4.33 (2H, br t, J = 4.8 Hz), 3.74 (2H, br t, J = 4.8 Hz), 3.67-3.63 (14H, m), 3.55-3.52 (2H, m), 3.36 (3H, s), 3.02 (1H, s). Pentaethylene glycol monomethyl ether (1.54 g, 6.1 mmol), ethyl acetate (10 mL), di (N-succinimidyl) carbonate (1.77 g, 6.9 mmol), triethylamine (2.6 mL, 19 mmol), 4-ethynylaniline (962.2 mg, 8.2 mmol) and 4-dimethylaminopyridine (78.5 mg, 0.64 mmol) were used as starting materials and were treated in the same manner as in Reference Example 29 to give the title compound (1.20 g, 50%) as an orange oil. .
1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (2H, br d, J = 8.8 Hz), 7.37 (2H, br d, J = 8.8 Hz), 7.14 (1H, br s), 4.33 (2H, br t, J = 4.8 Hz), 3.74 (2H, br t, J = 4.8 Hz), 3.67-3.63 (14H, m), 3.55-3.52 (2H, m), 3.36 (3H, s), 3.02 (1H, s).
3,6,9,12-テトラオキサトリデカン酸の製造 Reference Example 37
Production of 3,6,9,12-tetraoxatridecanoic acid
1H NMR (400 MHz, CDCl3) δ 4.16 (2H, s), 3.78-3.75 (2H, m), 3.70-3.63 (8H, m), 3.59-3.57 (2H, m), 3.39 (3H, s). Tetraethylene glycol monomethyl ether (3.04 g, 19 mmol) was added to a solution of 60% sodium hydride (1.37 g, 34 mmol) in tetrahydrofuran (10 mL) under ice cooling, and the mixture was stirred for 20 minutes. To this solution, tert-butyl bromoacetate (4.31 g, 22 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 13 hours. To this solution, lithium hydroxide (1.73 g, 72 mmol) and water (15 mL) were further added, and the mixture was stirred for 4 hours under heating to reflux. The solution was diluted with water and washed with diethyl ether. The aqueous layer was adjusted to pH = 1 with 6N hydrochloric acid and extracted with dichloromethane / methanol (v / v) = 10/1. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.13 g, 52%) as an orange oil.
1 H NMR (400 MHz, CDCl 3 ) δ 4.16 (2H, s), 3.78-3.75 (2H, m), 3.70-3.63 (8H, m), 3.59-3.57 (2H, m), 3.39 (3H, s ).
3,6,9,12,15-ペンタオキサヘキサデカン酸の製造 Reference Example 38
Production of 3,6,9,12,15-pentaoxahexadecanoic acid
1H NMR (400 MHz, CDCl3) δ 4.16 (2H, s), 3.77-3.56 (16H, m), 3.39 (3H, s). 60% sodium hydride (2.20 g, 54.6 mmol), tetrahydrofuran (29 mL), tetraethylene glycol monomethyl ether (3.80 g, 18.2 mmol), tert-butyl bromoacetate (2.93 mL, 20.0 mmol), lithium hydroxide (1.30 g, 54.6 mmol) and water (3.6 mL) were used as raw materials and the same operation as in Reference Example 37 was carried out to obtain the title compound (2.79 g, 58%) as a brown oily substance.
1 H NMR (400 MHz, CDCl 3 ) δ 4.16 (2H, s), 3.77-3.56 (16H, m), 3.39 (3H, s).
3,6,9,12,15,18-ヘキサオキサノナデカン酸の製造 Reference Example 39
Production of 3,6,9,12,15,18-hexaoxanonadecanoic acid
1H NMR (400 MHz, CDCl3) δ 4.17 (2H, s), 3.75-3.55 (20H, m), 3.38 (3H, s). 60% sodium hydride (600 mg, 15 mmol), tetrahydrofuran (8 mL), pentaethylene glycol monomethyl ether (1.26 g, 5.0 mmol), tert-butyl bromoacetate (0.81 mL, 5.5 mmol), lithium hydroxide (359.3 mg, 15 mmol) and water (1 mL) were used as raw materials and the same operation as in Reference Example 37 was performed to obtain the title compound (1.38 g, 89%) as a colorless oil.
1 H NMR (400 MHz, CDCl 3 ) δ 4.17 (2H, s), 3.75-3.55 (20H, m), 3.38 (3H, s).
N-(3-エチニルフェニル)-2,5,8,11,14,17-ヘキサオキサノナデカン-19-アミドの製造 Reference Example 40
Preparation of N- (3-ethynylphenyl) -2,5,8,11,14,17-hexaoxanonadecane-19-amide
1H NMR (400 MHz, CDCl3) δ 8.89 (1H, s), 7.74 (1H, t, J = 1.6 Hz), 7.67 (1H, dt, J = 8.0, 1.6 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.24 (1H, dt, J = 8.0, 1.6 Hz ), 4.10 (2H, s), 3.77-3.75 (2H, m), 3.72-3.71 (4H, m), 3.69-3.67 (2H, m), 3.63-3.59 (10H, m), 3.53-3.51 (2H, m), 3.36 (3H, s), 3.10 (1H, s). To a solution of 3,6,9,12,15,18-hexaoxanonadecanoic acid (214.4 mg, 0.70 mmol) in dichloromethane (3 mL), add 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride Salt (238.5 mg, 1.2 mmol), 4-dimethylaminopyridine (161.1 mg, 1.3 mmol), and 3-ethynylaniline (116.3 mg, 0.99 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (218.2 mg, 77%) as an orange oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (1H, s), 7.74 (1H, t, J = 1.6 Hz), 7.67 (1H, dt, J = 8.0, 1.6 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.24 (1H, dt, J = 8.0, 1.6 Hz), 4.10 (2H, s), 3.77-3.75 (2H, m), 3.72-3.71 (4H, m), 3.69-3.67 (2H , m), 3.63-3.59 (10H, m), 3.53-3.51 (2H, m), 3.36 (3H, s), 3.10 (1H, s).
N-(4-エチニルフェニル)-2,5,8,11-テトラオキサトリデカン-13-アミドの製造 Reference Example 41
Preparation of N- (4-ethynylphenyl) -2,5,8,11-tetraoxatridecane-13-amide
1H NMR (400 MHz, CDCl3) δ 8.88 (1H, br s), 7.61 (2H, br d, J = 8.4 Hz), 7.45 (2H, br d, J = 8.4 Hz), 4.11 (2H, s), 3.77-3.60 (10H, m), 3.52-3.49 (2H, m), 3.34 (3H, s), 3.04 (1H, s). 3,6,9,12-Tetraoxatridecanoic acid (488.9 mg, 2.2 mmol), dichloromethane (3 mL), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (766.8 mg, 4.0 mmol), 4-dimethylaminopyridine (366.4 mg, 6.0 mmol), and 4-ethynylaniline (234.3 mg, 2.0 mmol) as starting materials and the same procedure as in Reference Example 40 was performed to give the title compound (257.8 mg, 40 mmol). %) As a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (1H, br s), 7.61 (2H, br d, J = 8.4 Hz), 7.45 (2H, br d, J = 8.4 Hz), 4.11 (2H, s ), 3.77-3.60 (10H, m), 3.52-3.49 (2H, m), 3.34 (3H, s), 3.04 (1H, s).
N-(4-エチニルフェニル)-2,5,8,11,14-ペンタオキサヘキサデカン-16-アミドの製造 Reference Example 42
Production of N- (4-ethynylphenyl) -2,5,8,11,14-pentaoxahexadecane-16-amide
1H NMR (400 MHz, CDCl3) δ 8.88 (1H, br s), 7.61 (2H, br d, J = 8.4 Hz), 7.45 (2H, br d, J = 8.4 Hz), 4.11 (2H, s), 3.77-3.59 (14H, m), 3.52-3.50 (2H, m), 3.36 (3H, s), 3.04 (1H, s). 3,6,9,12,15-pentaoxahexadecanoic acid (878.8 mg, 3.3 mmol), dichloromethane (5 mL), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (1.15 g, 6.0 mmol), 4-dimethylaminopyridine (1.47 g, 12 mmol), and 4-ethynylaniline (351.5 mg, 3.0 mmol) were used as starting materials, and were treated in the same manner as in Reference Example 40 to give the title compound (408.3 mg, 37%) was obtained as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (1H, br s), 7.61 (2H, br d, J = 8.4 Hz), 7.45 (2H, br d, J = 8.4 Hz), 4.11 (2H, s ), 3.77-3.59 (14H, m), 3.52-3.50 (2H, m), 3.36 (3H, s), 3.04 (1H, s).
N-(4-エチニルフェニル)-2,5,8,11,14,17-ヘキサオキサノナデカン-19-アミドの製造 Reference Example 43
Preparation of N- (4-ethynylphenyl) -2,5,8,11,14,17-hexaoxanonadecane-19-amide
1H NMR (400 MHz, CDCl3) δ 9.02 (1H, br s), 7.64 (2H, br d, J = 8.4 Hz), 7.44 (2H, br d, J = 8.4 Hz), 4.10 (2H, s), 3.77-3.74 (2H, m), 3.72-3.70 (4H, m), 3.68-3.66 (2H, m), 3.62-3.59 (10H, m), 3.52-3.50 (2H, m), 3.35 (3H, s), 3.11 (1H, s). 3,6,9,12,15,18-hexaoxanonadecanoic acid (220.3 mg, 0.71 mmol), dichloromethane (3 mL), 4-ethynylaniline (109.8 mg, 0.94 mmol), 1-ethyl-3- [ The title compound (3- (dimethylamino) propyl] carbodiimide hydrochloride (284.4 mg, 1.5 mmol) and 4-dimethylaminopyridine (173.5 mg, 1.4 mmol) were used as starting materials in the same manner as in Reference Example 40. 199.6 mg, 69%) was obtained as a red oil.
1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (1H, br s), 7.64 (2H, br d, J = 8.4 Hz), 7.44 (2H, br d, J = 8.4 Hz), 4.10 (2H, s ), 3.77-3.74 (2H, m), 3.72-3.70 (4H, m), 3.68-3.66 (2H, m), 3.62-3.59 (10H, m), 3.52-3.50 (2H, m), 3.35 (3H , s), 3.11 (1H, s).
N-(5-エチニルピリジン-2-イル)-2,5,8,11-テトラオキサトリデカン-13-アミドの製造 Reference Example 44
Preparation of N- (5-ethynylpyridin-2-yl) -2,5,8,11-tetraoxatridecane-13-amide
1H NMR (400 MHz, CDCl3) δ 9.24 (1H, br s), 8.42 (1H, br d, J = 2.4 Hz), 8.23 (1H, d, J = 8.8 Hz), 7.79 (1H, dd, J = 8.8, 2.4 Hz), 4.16 (2H, s), 3.79-3.77 (2H, m), 3.74-3.72 (6H, m), 3.66-3.63 (2H, m), 3.55-3.52 (2H, m), 3.37 (3H, s), 3.16 (1H, s). 3,6,9,12-Tetraoxatridecanoic acid (320.1 mg, 1.4 mmol) was added to 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (526.1 mg, 2.7 mmol), 4- Dimethylaminopyridine (664.6 mg, 5.4 mmol), dichloromethane (5 mL), and 5-ethynylpyridin-2-amine (239.6 mg, 2.0 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with 10% aqueous citric acid solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = ¼) to give the title compound (199.4 mg, 43%) as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (1H, br s), 8.42 (1H, br d, J = 2.4 Hz), 8.23 (1H, d, J = 8.8 Hz), 7.79 (1H, dd, J = 8.8, 2.4 Hz), 4.16 (2H, s), 3.79-3.77 (2H, m), 3.74-3.72 (6H, m), 3.66-3.63 (2H, m), 3.55-3.52 (2H, m) , 3.37 (3H, s), 3.16 (1H, s).
N-(5-エチニルピリジン-2-イル)-2,5,8,11,14-ペンタオキサヘキサデカン-16-アミドの製造 Reference Example 45
Preparation of N- (5-ethynylpyridin-2-yl) -2,5,8,11,14-pentaoxahexadecane-16-amide
1H NMR (400 MHz, CDCl3) δ 9.28 (1H, br s), 8.41 (1H, s), 8.21 (1H, d, J = 8.4 Hz), 7.78 (1H, br d, J = 8.4 Hz), 4.18 (2H, s), 3.79-3.77 (2H, m), 3.74-3.71 (6H, m), 3.66-3.63 (6H, m), 3.55-3.53 (2H, m), 3.36 (3H, s), 3.22 (1H, s). 3,6,9,12,15-pentaoxahexadecanoic acid (427.8 mg, 1.6 mmol), N, N-dimethylformamide (5 mL), O- (7-azabenzotriazol-1-yl) -N, N , N ', N'-Tetramethyluronium hexafluorophosphate (1.24 g, 3.3 mmol), N, N-diisopropylethylamine (1.2 mL, 6.9 mmol), and 5-ethynylpyridin-2-amine (181 mg , 1.5 mmol) as the starting material and the same operation as in Reference Example 44 gave the title compound (140.2 mg, 25%) as a red oil.
1 H NMR (400 MHz, CDCl 3 ) δ 9.28 (1H, br s), 8.41 (1H, s), 8.21 (1H, d, J = 8.4 Hz), 7.78 (1H, br d, J = 8.4 Hz) , 4.18 (2H, s), 3.79-3.77 (2H, m), 3.74-3.71 (6H, m), 3.66-3.63 (6H, m), 3.55-3.53 (2H, m), 3.36 (3H, s) , 3.22 (1H, s).
N-(5-エチニルピリジン-2-イル)-2,5,8,11,14,17-ヘキサオキサノナデカン-19-アミドの製造 Reference Example 46
Preparation of N- (5-ethynylpyridin-2-yl) -2,5,8,11,14,17-hexaoxanonadecane-19-amide
1H NMR (400 MHz, CDCl3) δ 9.27 (1H, br s), 8.41 (1H, br d, J = 2.0 Hz), 8.23 (1H, br d, J = 8.8 Hz), 7.79 (1H, dd, J = 8.8, 2.0 Hz), 4.16 (2H, s), 3.78-3.63 (18H, m), 3.55-3.54 (2H, m), 3.37 (3H, s), 3.16 (1H, s). 3,6,9,12,15,18-hexaoxanonadecanoic acid (315.0 mg, 1.0 mmol), dichloromethane (1 mL), N, N-dimethylformamide (3 mL), 1-ethyl-3- [3 -(Dimethylamino) propyl] carbodiimide hydrochloride (413.0 mg, 2.2 mmol), 4-dimethylaminopyridine (497.0 mg, 4.1 mmol), and 5-ethynylpyridin-2-amine (239.0 mg, 2.0 mmol) as raw materials The title compound (266.6 mg, 64%) was obtained as an orange solid by using in the same manner as in Reference Example 44.
1 H NMR (400 MHz, CDCl 3 ) δ 9.27 (1H, br s), 8.41 (1H, br d, J = 2.0 Hz), 8.23 (1H, br d, J = 8.8 Hz), 7.79 (1H, dd , J = 8.8, 2.0 Hz), 4.16 (2H, s), 3.78-3.63 (18H, m), 3.55-3.54 (2H, m), 3.37 (3H, s), 3.16 (1H, s).
N-(6-エチニルピリジン-3-イル)-2,5,8,11-テトラオキサトリデカン-13-アミドの製造 Reference Example 47
Preparation of N- (6-ethynylpyridin-3-yl) -2,5,8,11-tetraoxatridecane-13-amide
1H NMR (400 MHz, CDCl3) δ 9.16 (1H, br s), 8.66 (1H, br s), 8.28 (1H, dd, J = 8.4, 2.4 Hz), 7.47 (1H, br d, J = 8.4 Hz), 4.14 (2H, s), 3.77-3.63 (10H, m), 3.51-3.49 (2H, m), 3.32 (3H, s), 3.14 (1H, s). 3,6,9,12-tetraoxatridecanoic acid (446.5 mg, 2.0 mmol), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (776.0 mg, 4.0 mmol), dichloromethane (10 mL), triethylamine (1.1 mL, 7.9 mmol), 6-ethynylpyridin-3-amine (255.2 mg, 2.2 mmol), and 4-dimethylaminopyridine (30.5 mg, 0.25 mmol) were used as starting materials. The same operation was performed to obtain the title compound (96.7 mg, 15%) as a brown oily substance.
1 H NMR (400 MHz, CDCl 3 ) δ 9.16 (1H, br s), 8.66 (1H, br s), 8.28 (1H, dd, J = 8.4, 2.4 Hz), 7.47 (1H, br d, J = 8.4 Hz), 4.14 (2H, s), 3.77-3.63 (10H, m), 3.51-3.49 (2H, m), 3.32 (3H, s), 3.14 (1H, s).
2-[2-(2-メトキシエトキシ)エトキシ]エチル4-メチルベンゼンスルホナートの製造 Reference Example 48
Preparation of 2- [2- (2-methoxyethoxy) ethoxy] ethyl 4-methylbenzenesulfonate
1H NMR (400 MHz, CDCl3) δ 7.80 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 4.16 (2H, br t, J = 4.8 Hz), 3.70-3.68 (2H, m), 3.62-3.59 (6H, m), 3.54-3.52 (2H, m), 3.37 (3H, s), 2.45 (3H, s). Triethylamine (1.27 mL, 9.15 mmol) and triethylene glycol monomethyl ether (525 μL, 3.05 mmol) were added to a solution of p-toluenesulfonyl chloride (872.2 mg, 4.58 mmol) in dichloromethane (3 mL), and the mixture was stirred overnight at room temperature. . Methanol (0.5 mL) was further added to this solution, and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, the insoluble material was removed by filtration, and the insoluble material was washed with diethyl ether and isopropanol. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (796.9 mg, 82%) as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 4.16 (2H, br t, J = 4.8 Hz), 3.70- 3.68 (2H, m), 3.62-3.59 (6H, m), 3.54-3.52 (2H, m), 3.37 (3H, s), 2.45 (3H, s).
2,5,8,11-テトラオキサトリデカン-13-イル 4-メチルベンゼンスルホナートの製造 Reference Example 49
Preparation of 2,5,8,11-tetraoxatridecan-13-yl 4-methylbenzenesulfonate
1H NMR (400 MHz, CDCl3) δ 7.80 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 4.16 (2H, br t, J = 5.0 Hz), 3.70-3.68 (2H, m), 3.65-3.62 (6H, m), 3.59-3.57 (4H, m), 3.55-3.53 (2H, m), 3.37 (3H, s), 2.45 (3H, s). p-Toluenesulfonyl chloride (7.19 g, 37.7 mmol), dichloromethane (25 mL), triethylamine (10.5 mL, 75.3 mmol), and tetraethylene glycol monomethyl ether (5 mL, 25.1 mmol) were used as raw materials. The same operation was performed to obtain the title compound (8.24 g, 90%) as a brown oily substance.
1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 4.16 (2H, br t, J = 5.0 Hz), 3.70- 3.68 (2H, m), 3.65-3.62 (6H, m), 3.59-3.57 (4H, m), 3.55-3.53 (2H, m), 3.37 (3H, s), 2.45 (3H, s).
2,5,8,11,14-ペンタオキサヘキサデカン-16-イル 4-メチルベンゼンスルホナートの製造 Reference Example 50
Preparation of 2,5,8,11,14-pentaoxahexadecan-16-yl 4-methylbenzenesulfonate
1H NMR (400 MHz, CDCl3) δ 7.80 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 4.16 (2H, br t, J = 4.4 Hz), 3.70-3.58 (16H, m), 3.55-3.54 (2H, m), 3.37 (3H, br s), 2.45 (3H, s). p-Toluenesulfonyl chloride (3.06 g, 16.1 mmol), dichloromethane (12 mL), triethylamine (4.5 mL, 32.1 mmol), and pentaethylene glycol monomethyl ether (2.5 mL, 10.7 mmol) were used as raw materials. The same operation was performed to obtain the title compound (3.14 g, 72%) as a brown oily substance.
1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 4.16 (2H, br t, J = 4.4 Hz), 3.70- 3.58 (16H, m), 3.55-3.54 (2H, m), 3.37 (3H, br s), 2.45 (3H, s).
3-エチニル-N-(2-メトキシエチル)アニリンの製造 Reference Example 51
Preparation of 3-ethynyl-N- (2-methoxyethyl) aniline
1H NMR (400 MHz, CDCl3) δ 7.11 (1H, t, J = 7.5 Hz), 6.85 (1H, br d, J = 7.5 Hz), 6.74 (1H, t, J = 2.2 Hz), 6.62 (1H, br dd, J = 7.5, 2.2 Hz), 4.06 (1H, br s), 3.59 (2H, t, J = 5.2 Hz), 3.38 (3H, s), 3.27 (2H, t, J = 5.2 Hz), 3.00 (1H, s). To a solution of cesium carbonate (1.37 g, 4.2 mmol) and potassium iodide (84.0 mg, 0.52 mmol) in N, N-dimethylformamide (8 mL), add 3-ethynylaniline (288 μL, 2.6 mmol) and 1-bromo- 2-Methoxyethane (360 μL, 3.8 mmol) was added, and the mixture was stirred at 100 ° C. overnight. The solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane → hexane / ethyl acetate (v / v) = 96/4) to give the title compound (132.2 mg, 29%) as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.11 (1H, t, J = 7.5 Hz), 6.85 (1H, br d, J = 7.5 Hz), 6.74 (1H, t, J = 2.2 Hz), 6.62 ( 1H, br dd, J = 7.5, 2.2 Hz), 4.06 (1H, br s), 3.59 (2H, t, J = 5.2 Hz), 3.38 (3H, s), 3.27 (2H, t, J = 5.2 Hz ), 3.00 (1H, s).
3-エチニル-N-[2-(2-メトキシエトキシ)エチル]アニリンの製造 Reference Example 52
Preparation of 3-ethynyl-N- [2- (2-methoxyethoxy) ethyl] aniline
1H NMR (400 MHz, CDCl3) δ 7.10 (1H, t, J = 7.6 Hz), 6.84 (1H, br d, J = 7.6 Hz), 6.74 (1H, t, J = 2.2 Hz), 6.62 (1H, br dd, J = 7.6, 2.2 Hz), 4.16 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.65-3.63 (2H, m), 3.57-3.54 (2H, m), 3.40 (3H, s), 3.31-3.27 (2H, m), 3.00 (1H, s). Cesium carbonate (1.37 g, 4.2 mmol), potassium iodide (84.0 mg, 0.52 mmol), N, N-dimethylformamide (8 mL), 3-ethynylaniline (288 μL, 2.6 mmol), and 1-bromo-2 The title compound (155.0 mg, 28%) was obtained as a brown oil by operating in the same manner as in Reference Example 51 using-(2-methoxyethoxy) ethane (517 μL, 3.8 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 7.10 (1H, t, J = 7.6 Hz), 6.84 (1H, br d, J = 7.6 Hz), 6.74 (1H, t, J = 2.2 Hz), 6.62 ( 1H, br dd, J = 7.6, 2.2 Hz), 4.16 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.65-3.63 (2H, m), 3.57-3.54 (2H, m) , 3.40 (3H, s), 3.31-3.27 (2H, m), 3.00 (1H, s).
3-エチニル-N-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}アニリンの製造 Reference Example 53
Preparation of 3-ethynyl-N- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} aniline
1H NMR (400 MHz, CDCl3) δ 7.10 (1H, t, J = 7.9 Hz), 6.84 (1H, br d, J = 7.9 Hz), 6.74 (1H, t, J = 2.2 Hz), 6.62 (1H, br dd, J = 7.9, 2.2 Hz), 4.20 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.67-3.64 (6H, m), 3.57-3.55 (2H, m), 3.39 (3H, s), 3.28 (2H, br m), 3.00 (1H, s). To a solution of 2- [2- (2-methoxyethoxy) ethoxy] ethyl 4-methylbenzenesulfonate (223.0 mg, 0.7 mmol) in acetonitrile (4 mL), potassium carbonate (194.0 mg, 1.4 mmol), potassium iodide ( 29.0 mg, 0.18 mmol) and 3-ethynylaniline (96 μL, 0.85 mmol) were added, and the mixture was stirred overnight with heating under reflux. Insoluble materials were removed from the resulting solution by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 60/40 → 40/60) to give the title compound (100.2 mg, 54%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.10 (1H, t, J = 7.9 Hz), 6.84 (1H, br d, J = 7.9 Hz), 6.74 (1H, t, J = 2.2 Hz), 6.62 ( 1H, br dd, J = 7.9, 2.2 Hz), 4.20 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.67-3.64 (6H, m), 3.57-3.55 (2H, m) , 3.39 (3H, s), 3.28 (2H, br m), 3.00 (1H, s).
4-エチニル-N-[2-(2-メトキシエトキシ)エチル]アニリンの製造 Reference Example 54
Preparation of 4-ethynyl-N- [2- (2-methoxyethoxy) ethyl] aniline
1H NMR (400 MHz, CDCl3) δ 7.30 (2H, d, J = 8.8 Hz), 6.52 (2H, d, J = 8.8 Hz), 4.33 (1H, br s), 3.69 (2H, t, J = 5.2 Hz), 3.64-3.62 (2H, m), 3.56-3.54 (2H, m), 3.39 (3H, s), 3.30-3.29 (2H, m), 2.95 (1H, s). Cesium carbonate (1.37 g, 4.2 mmol), potassium iodide (84.0 mg, 0.52 mmol), N, N-dimethylformamide (8 mL), 4-ethynylaniline (300.0 mg, 2.6 mmol), and 1-bromo-2 The title compound (100.0 mg, 18%) was obtained as a pale yellow oil by operating in the same manner as in Reference Example 51 using-(2-methoxyethoxy) ethane (777 μL, 5.8 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (2H, d, J = 8.8 Hz), 6.52 (2H, d, J = 8.8 Hz), 4.33 (1H, br s), 3.69 (2H, t, J = 5.2 Hz), 3.64-3.62 (2H, m), 3.56-3.54 (2H, m), 3.39 (3H, s), 3.30-3.29 (2H, m), 2.95 (1H, s).
4-エチニル-N-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}アニリンの製造 Reference Example 55
Preparation of 4-ethynyl-N- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} aniline
1H NMR (400 MHz, CDCl3) δ 7.30 (2H, d, J = 8.8 Hz), 6.53 (2H, d, J = 8.8 Hz), 4.36 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.65-3.64 (6H, m), 3.57-3.54 (2H, m), 3.38 (3H, s), 3.32-3.28 (2H, m), 2.95 (1H, s). 2- [2- (2-methoxyethoxy) ethoxy] ethyl 4-methylbenzenesulfonate (669.0 mg, 2.1 mmol), acetonitrile (12 mL), potassium carbonate (582.0 mg, 4.2 mmol), potassium iodide (87.0 mg , 0.52 mmol), and 4-ethynylaniline (300.0 mg, 2.6 mmol) as starting materials, and the same operation as in Reference Example 53 gave the title compound (224.9 mg, 40%) as a brown oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (2H, d, J = 8.8 Hz), 6.53 (2H, d, J = 8.8 Hz), 4.36 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.65-3.64 (6H, m), 3.57-3.54 (2H, m), 3.38 (3H, s), 3.32-3.28 (2H, m), 2.95 (1H, s).
N-(4-エチニルフェニル)-2,5,8,11-テトラオキサトリデカン-13-アミンの製造 Reference Example 56
Production of N- (4-ethynylphenyl) -2,5,8,11-tetraoxatridecan-13-amine
1H NMR (400 MHz, CDCl3) δ 7.30 (2H, d, J = 8.8 Hz), 6.53 (2H, d, J = 8.8 Hz), 4.36 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.66-3.63 (10H, m), 3.55-3.53 (2H, m), 3.37 (3H, s), 3.32-3.28 (2H, m), 2.95 (1H, s). 2,5,8,11-tetraoxatridecan-13-yl 4-methylbenzenesulfonate (1.00 g, 2.8 mmol), acetonitrile (20 mL), potassium carbonate (1.40 g, 10 mmol), potassium iodide ( 227 mg, 1.4 mmol) and 4-ethynylaniline (800.0 mg, 6.8 mmol) were used as starting materials and were treated in the same manner as in Reference Example 53 to give the title compound (446.0 mg, 53%) as a yellow oil. .
1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (2H, d, J = 8.8 Hz), 6.53 (2H, d, J = 8.8 Hz), 4.36 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.66-3.63 (10H, m), 3.55-3.53 (2H, m), 3.37 (3H, s), 3.32-3.28 (2H, m), 2.95 (1H, s).
N-(4-エチニルフェニル)-2,5,8,11,14-ペンタオキサヘキサデカン-16-アミンの製造 Reference Example 57
Production of N- (4-ethynylphenyl) -2,5,8,11,14-pentaoxahexadecan-16-amine
1H NMR (400 MHz, CDCl3) δ 7.30 (2H, d, J = 8.8 Hz), 6.53 (2H, d, J = 8.8 Hz), 4.39 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.66-3.62 (14H, m), 3.55-3.52 (2H, m), 3.37 (3H, s), 3.31-3.28 (2H, m), 2.95 (1H, s). 2,5,8,11,14-pentaoxahexadecan-16-yl 4-methylbenzenesulfonate (694.3 mg, 1.7 mmol), acetonitrile (12 mL), potassium carbonate (885.0 mg, 6.4 mmol), potassium iodide (141.8 mg, 0.85 mmol) and 4-ethynylaniline (500.0 mg, 4.3 mmol) were used as starting materials and were treated in the same manner as in Reference Example 53 to give the title compound (104.0 mg, 17%) as a yellow oil. It was.
1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (2H, d, J = 8.8 Hz), 6.53 (2H, d, J = 8.8 Hz), 4.39 (1H, br s), 3.70 (2H, t, J = 5.2 Hz), 3.66-3.62 (14H, m), 3.55-3.52 (2H, m), 3.37 (3H, s), 3.31-3.28 (2H, m), 2.95 (1H, s).
2,2’-ジチオサリチル酸ジクロリドの製造 Reference Example 58
Production of 2,2'-dithiosalicylic acid dichloride
1H NMR (400 MHz, CDCl3) δ 8.40 (2H, dd, J = 8.0, 1.4 Hz), 7.77 (2H, dd, J = 8.0, 1.1 Hz), 7.55 (2H, td, J =8.0, 1.4 Hz), 7.24 (2H, td, J = 8.0, 1.1 Hz). To a solution of 2,2'-dithiosalicylic acid (25.0 g, 81.6 mmol) in dichloromethane (220 mL) was added oxalyl chloride (25 mL, 291.5 mmol) and N, N-dimethylformamide (150 μL, 1.94 mmol) at room temperature. For 18 hours. The resulting solution was further stirred at 50 ° C. for 24 hours, and then the solvent was distilled off under reduced pressure. The obtained solid was washed with hexane at 0 ° C. and dried to give the title compound (24.9 g, 89%) as a pale-yellow solid.
1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (2H, dd, J = 8.0, 1.4 Hz), 7.77 (2H, dd, J = 8.0, 1.1 Hz), 7.55 (2H, td, J = 8.0, 1.4 Hz), 7.24 (2H, td, J = 8.0, 1.1 Hz).
2,2’-ジチオビス(N-メチルベンズアミド) の製造 Reference Example 59
Production of 2,2'-dithiobis (N-methylbenzamide)
1H NMR (400 MHz, CDCl3) δ 7.75 (2H, br d, J = 7.6 Hz), 7.47 (2H, dd, J = 7.6, 1.2 Hz), 7.36 (2H, td, J = 7.6, 1.2 Hz), 7.24 (2H, td, J = 7.6, 1.2 Hz), 6.13 (2H, br m), 2.97 (6H, d, J = 4.8 Hz). To a solution of 2,2'-dithiosalicylic acid dichloride (12.5 g, 36.4 mmol) in tetrahydrofuran (56 mL) was added methylamine (2M tetrahydrofuran solution) (80 mL, 160.2 mmol) at 0 ° C, and the mixture was stirred at room temperature for 16 hours. . Water was added to this solution and stirred for 30 minutes, and then the solvent was distilled off under reduced pressure. The obtained solid was washed with water and dried to give the title compound (11.7 g, 96%) as a pale-yellow solid.
1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (2H, br d, J = 7.6 Hz), 7.47 (2H, dd, J = 7.6, 1.2 Hz), 7.36 (2H, td, J = 7.6, 1.2 Hz ), 7.24 (2H, td, J = 7.6, 1.2 Hz), 6.13 (2H, br m), 2.97 (6H, d, J = 4.8 Hz).
2-メルカプト-N-メチルベンズアミドの製造 Reference Example 60
Production of 2-mercapto-N-methylbenzamide
1H NMR (400 MHz, CDCl3) δ 7.42 (1H, dd, J = 7.8, 1.5 Hz), 7.32 (1H, dd, J = 7.8, 1.3 Hz), 7.25 (1H, td, J = 7.8, 1.5 Hz), 7.13 (1H, td, J = 7.8, 1.3 Hz), 6.12 (1H, br m), 4.77 (1H, s), 2.99 (3H, d, J = 4.8 Hz). To a solution of 2,2'-dithiobis (N-methylbenzamide) (11.7 g, 35.1 mmol) in ethanol (110 mL) was added sodium borohydride (3.05 g, 80.7 mmol) at 0 ° C and stirred at room temperature for 16 hours. did. The solution was diluted with water and adjusted to pH = 1 with 2N hydrochloric acid, and then the solvent was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound (7.72 g, 66%) as a pale yellow solid.
1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (1H, dd, J = 7.8, 1.5 Hz), 7.32 (1H, dd, J = 7.8, 1.3 Hz), 7.25 (1H, td, J = 7.8, 1.5 Hz), 7.13 (1H, td, J = 7.8, 1.3 Hz), 6.12 (1H, br m), 4.77 (1H, s), 2.99 (3H, d, J = 4.8 Hz).
6-ヨード-1H-インダゾールの製造 Reference Example 61
Production of 6-iodo-1H-indazole
1H NMR (400 MHz, CDCl3) δ 10.24 (1H, br s), 8.04 (1H, br s), 7.92 (1H, br s), 7.51 (1H, br d, J = 8.4 Hz), 7.46 (1H, dd, J = 8.4, 1.2 Hz). To a suspension of 6-aminoindazole (10.4 g, 78 mmol) in water (30 mL), an aqueous solution of concentrated hydrochloric acid (35 mL, 420 mmol) and sodium nitrite (6.64 g, 96 mmol) (30 mL) ) Was added at 0 ° C and stirred at 0 ° C for 30 minutes. Subsequently, an aqueous solution (30 mL) of potassium iodide (15.91 g, 96 mmol) was added to this solution at 0 ° C., and the mixture was stirred at room temperature for 30 minutes, and then dichloromethane (80 mL) was added thereto, and then at 40 ° C. for 2 hours. Stir. The reaction solution was cooled to 0 ° C., adjusted to pH = 14 with 3N aqueous sodium hydroxide solution, and the precipitate was collected by filtration. The obtained precipitate was washed with 10% sodium thiosulfate, dissolved in tetrahydrofuran, and silica gel was added. After stirring at room temperature for 1 hour, hexane (600 mL) was added and filtered. The residue was washed twice with a THF / hexane (1/3 (v / v)) solution, and the solvent was evaporated under reduced pressure to give the title compound (15.23 g, 80%) as an orange powder.
1 H NMR (400 MHz, CDCl 3 ) δ 10.24 (1H, br s), 8.04 (1H, br s), 7.92 (1H, br s), 7.51 (1H, br d, J = 8.4 Hz), 7.46 ( (1H, dd, J = 8.4, 1.2 Hz).
2-{(1H-インダゾール-6-イル)チオ}-N-メチルベンズアミドの製造 Reference Example 62
Preparation of 2-{(1H-indazol-6-yl) thio} -N-methylbenzamide
1H NMR (400 MHz, DMSO-d6) δ 13.13 (1H, br s), 8.36 (1H, br q, J = 4.4 Hz), 8.10 (1H, s), 7.78 (1H, br d, J = 8.4 Hz), 7.59 (1H, br s), 7.48-7.46 (1H, m), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.25 (1H, td, J = 7.6, 1.6 Hz), 7.08 (1H, dd, J = 8.4, 1.6 Hz), 6.99-6.97 (1H, m), 2.76 (3H, d, J = 4.4 Hz). 6-iodo-1H-indazole (5.51 g, 22 mmol), 2-mercapto-N-methylbenzamide (5.16 g, 31 mmol), Pd 2 (dba) 3 (1.02 g, 1.1 mmol), 4,5-bis N, N-dimethylformamide (25 mL) was added to (diphenylphosphino) -9,9-dimethylxanthene (1.46 g, 2.5 mmol) and cesium hydroxide monohydrate (5.67 g, 33 mmol), The mixture was stirred at 100 ° C. for 4.5 hours under an argon atmosphere. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 1/3) to give the title compound (6.14 g, 96%) as a pale orange solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.13 (1H, br s), 8.36 (1H, br q, J = 4.4 Hz), 8.10 (1H, s), 7.78 (1H, br d, J = 8.4 Hz), 7.59 (1H, br s), 7.48-7.46 (1H, m), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.25 (1H, td, J = 7.6, 1.6 Hz), 7.08 (1H, dd, J = 8.4, 1.6 Hz), 6.99-6.97 (1H, m), 2.76 (3H, d, J = 4.4 Hz).
2-{(3-ヨード-1H-インダゾール-6-イル)チオ}-N-メチルベンズアミドの製造 Reference Example 63
Preparation of 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide
1H NMR (400 MHz, DMSO-d6) δ 13.55 (1H, br s), 8.37 (1H, br q, J = 4.4 Hz), 7.56 (1H, br s), 7.49-7.47 (1H, m), 7.44 (1H, br d, J = 8.8 Hz), 7.31 (1H, td, J = 7.6, 2.0 Hz), 7.28 (1H, td, J = 7.6, 2.0 Hz), 7.14 (1H, dd, J = 8.8, 1.6 Hz), 7.04-7.02 (1H, m), 2.76 (3H, d, J = 4.4 Hz). To a solution of 2-{(1H-indazol-6-yl) thio} -N-methylbenzamide (7.32 g, 26 mmol) and potassium carbonate (7.36 g, 53 mmol) in N, N-dimethylformamide (30 mL), A solution of iodine (11.09 g, 46 mmol) in N, N-dimethylformamide (20 mL) was added at 0 ° C. over 30 minutes, and the mixture was stirred at room temperature for 3.5 hours. After the solvent was distilled off from the reaction solution under reduced pressure, the residue was dissolved in ethyl acetate and washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained solid was washed with hexane / ethyl acetate (1/1 (v / v)) solution and dried to give the title compound (7.60 g, 72%) as a pale-yellow solid.
1H NMR (400 MHz, DMSO-d 6 ) δ 13.55 (1H, br s), 8.37 (1H, br q, J = 4.4 Hz), 7.56 (1H, br s), 7.49-7.47 (1H, m), 7.44 (1H, br d, J = 8.8 Hz), 7.31 (1H, td, J = 7.6, 2.0 Hz), 7.28 (1H, td, J = 7.6, 2.0 Hz), 7.14 (1H, dd, J = 8.8 , 1.6 Hz), 7.04-7.02 (1H, m), 2.76 (3H, d, J = 4.4 Hz).
トリエチレングリコールモノtert-ブチルジメチルシリルエーテルの製造 Reference Example 64
Production of triethylene glycol mono tert-butyldimethylsilyl ether
1H NMR (400 MHz, CDCl3) δ 3.79-3.72 (4H, m), 3.67-3.54 (8H, m), 0.90 (9H, s), 0.07 (6H, s). Triethylene glycol (2.2 mL, 16.5 mmol) was added to a tetrahydrofuran (88 mL) solution of 60% sodium hydride (713 mg, 17.8 mmol) at 0 ° C., and the mixture was stirred at room temperature for 40 minutes. To this solution was added tert-butyldimethylchlorosilane (2.74 g, 18.2 mmol), and the mixture was stirred at room temperature for 23 hours. Water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.19 g, quant.) As a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 3.79-3.72 (4H, m), 3.67-3.54 (8H, m), 0.90 (9H, s), 0.07 (6H, s).
2-(2,2,3,3-テトラメチル-4,7,10-トリオキサ-3-シラドデカン-12-イル)イソインドリン-1,3-ジオンの製造 Reference Example 65
Preparation of 2- (2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl) isoindoline-1,3-dione
1H NMR (400 MHz, CDCl3) δ 7.84 (2H, dd, J = 5.2, 3.2 Hz), 7.71 (2H, dd, J = 5.2, 3.2 Hz), 3.90 (2H, t, J = 6.0 Hz), 3.74 (2H, t, J = 6.0 Hz), 3.70 (2H, t, J = 5.6 Hz), 3.65-3.59 (4H, m), 3.50 (2H, t, J = 5.6 Hz), 0.87 (s, 9H), 0.04 (s, 6H). To a solution of phthalimide (1.15 g, 7.82 mmol) and triphenylphosphine (2.06 g, 7.85 mmol) in tetrahydrofuran (50 mL) was added triethylene glycol mono tert-butyldimethylsilyl ether (1.3 g, 4.92 mmol) and diethylazodicarboxy. Lat (2.2 mol / L toluene solution) (2.4 mL, 5.3 mmol) was added at room temperature and stirred overnight. Ethanol (20 mL) was further added, and the mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. Ethyl acetate (12.5 mL) and hexane (12.5 mL) were added to the residue, and the insoluble material was removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 5/95 → 0/100) to give the title compound (822 mg, 42%) as colorless Obtained as an oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (2H, dd, J = 5.2, 3.2 Hz), 7.71 (2H, dd, J = 5.2, 3.2 Hz), 3.90 (2H, t, J = 6.0 Hz) , 3.74 (2H, t, J = 6.0 Hz), 3.70 (2H, t, J = 5.6 Hz), 3.65-3.59 (4H, m), 3.50 (2H, t, J = 5.6 Hz), 0.87 (s, 9H), 0.04 (s, 6H).
2-[2-(2-アミノエトキシ)エトキシ]エタノールの製造 Reference Example 66
Production of 2- [2- (2-aminoethoxy) ethoxy] ethanol
1H NMR (400 MHz, CDCl3) δ 3.73 (2H, t, J = 4.4 Hz), 3.69-3.64 (6H, m), 3.59 (2H, t, J = 4.4 Hz), 3.03 (2H, br t, J = 4.4 Hz). 2- (2,2,3,3-Tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl) isoindoline-1,3-dione (822 mg, 2.09 mmol) in ethanol (120 mL ) Was added hydrazine monohydrate (322.6 μL, 9.2 mmol), and the mixture was stirred overnight with heating under reflux. After cooling to room temperature, concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred for 2 hours with heating under reflux. The solution was cooled to room temperature, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue and washed with ethyl acetate. The aqueous layer was adjusted to pH = 9 with 3N aqueous sodium hydroxide solution and washed with dichloromethane / methanol (v / v) = 10/1. After the solvent was distilled off from the aqueous layer under reduced pressure, dichloromethane was added to the residue. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to give the title compound (239.1 mg, 77%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 3.73 (2H, t, J = 4.4 Hz), 3.69-3.64 (6H, m), 3.59 (2H, t, J = 4.4 Hz), 3.03 (2H, br t , J = 4.4 Hz).
1-(4-エチニルフェニル)-3-{2-[2-(2-ヒドロキシエトキシ)エトキシ]エチル}ウレアの製造 Reference Example 67
Preparation of 1- (4-ethynylphenyl) -3- {2- [2- (2-hydroxyethoxy) ethoxy] ethyl} urea
1H NMR (400 MHz, CDCl3) δ 8.30 (1H, br s), 7.32 (4H, m), 6.22 (1H, br t, J = 4.4 Hz), 4.37 (1H, br s), 3.72 (2H, br t, J = 4.4 Hz), 3.55-3.53 (6H, m), 3.49 (2H, t, J = 4.4 Hz), 3.36-3.34 (2H, m), 3.05 (1H, s). 4-Ethynylaniline (170.4 mg, 1.5 mmol) was added to a solution of 4-nitrophenyl chloroformate (289.3 mg, 1.4 mmol) in tetrahydrofuran (6.8 mL), stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure. Left. To a solution of the obtained crude product in dichloromethane (4 mL), 2- [2- (2-aminoethoxy) ethoxy] ethanol (239 mg, 1.6 mmol) in dichloromethane (4 mL) and triethylamine (303 μL, 2.2 mmol) was added, and the mixture was stirred overnight at room temperature, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol (v / v) = 100/0 → 90/10) to give the title compound (325.4 mg, 77%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (1H, br s), 7.32 (4H, m), 6.22 (1H, br t, J = 4.4 Hz), 4.37 (1H, br s), 3.72 (2H , br t, J = 4.4 Hz), 3.55-3.53 (6H, m), 3.49 (2H, t, J = 4.4 Hz), 3.36-3.34 (2H, m), 3.05 (1H, s).
1-{2-[2-(2-アミノエトキシ)エトキシ]エチル}-3-(4-エチニルフェニル)ウレアの製造 Reference Example 68
Preparation of 1- {2- [2- (2-aminoethoxy) ethoxy] ethyl} -3- (4-ethynylphenyl) urea
1H NMR (400 MHz, CDCl3) δ 8.71 (1H, br s), 7.37 (4H, m), 5.85 (1H, br s), 3.68-3.58 (8H, m), 3.49-3.46 (2H, m), 3.00-2.98 (3H, m), 1.73 (2H, br s). 4-Ethynylaniline (200 mg, 1.7 mmol) was added to a solution of 4-nitrophenyl chloroformate (341 mg, 1.7 mmol) in tetrahydrofuran (7.5 mL), stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure. Left. A solution of the obtained crude product in dichloromethane (10 mL) was dissolved in 2,2 '-[1,2-ethanediylbis (oxy)] bisethanamine (496 μL, 3.4 mmol) in dichloromethane (20 mL) at 0 ° C. After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99/1 → 90/10) to give the title compound (417 mg, 84%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (1H, br s), 7.37 (4H, m), 5.85 (1H, br s), 3.68-3.58 (8H, m), 3.49-3.46 (2H, m ), 3.00-2.98 (3H, m), 1.73 (2H, br s).
tert-ブチル N-{2-[2-(2-アミノエトキシ)エトキシ]エチル}カルバメートの製造 Reference Example 69
Preparation of tert-butyl N- {2- [2- (2-aminoethoxy) ethoxy] ethyl} carbamate
1H NMR (400 MHz, CDCl3) δ 5.13 (1H, br s), 3.62-3.49 (10H, m), 3.33 (2H, br s), 2.88 (2H, t, J = 5.2 Hz), 1.45 (9H, s). Di-tert-butyl dicarbonate (30% tetrahydrofuran solution) (5.1 mL, 6.2 mmol) in dichloromethane (29 mL) was added to 2,2 '-[1,2-ethanediylbis (oxy)] bisethanamine (2 mL , 13.6 mmol) and diisopropylethylamine (2.4 mL, 13.8 mmol) were added, and the mixture was stirred at room temperature for 4 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol / triethylamine (v / v / v) = 18/1/1) to obtain the title compound (810 mg, 53%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 5.13 (1H, br s), 3.62-3.49 (10H, m), 3.33 (2H, br s), 2.88 (2H, t, J = 5.2 Hz), 1.45 ( 9H, s).
tert-ブチル (2-{2-[2-(ジメチルアミノ)エトキシ]エトキシ}エチル)カルバメートの製造 Reference Example 70
Preparation of tert-butyl (2- {2- [2- (dimethylamino) ethoxy] ethoxy} ethyl) carbamate
1H NMR (400 MHz, CDCl3) δ 5.22 (1H, br s), 3.63-3.61 (6H, m), 3.54 (2H, br t, J = 4.8 Hz), 3.32-3.29 (2H, m), 2.60 (2H, br t, J = 5.6 Hz), 2.33 (6H, s), 1.44 (9H, 9s). tert-butyl {2- [2- (2-aminoethoxy) ethoxy] ethyl} carbamate (810 mg, 3.3 mmol), formaldehyde (37% aqueous solution) (8 mL, 98.6 mmol), and acetic acid (5.6 mL, 97.9 mmol) ) In methanol (20 mL) was added sodium triacetoxyborohydride (1.04 g, 4.9 mmol) at 0 ° C., and the mixture was stirred at room temperature for 3 hours, and then a saturated aqueous potassium carbonate solution was added. This solution was extracted with dichloromethane / methanol (v / v) = 10/1, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 4/1) to give the title compound (277.5 mg, 31%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 5.22 (1H, br s), 3.63-3.61 (6H, m), 3.54 (2H, br t, J = 4.8 Hz), 3.32-3.29 (2H, m), 2.60 (2H, br t, J = 5.6 Hz), 2.33 (6H, s), 1.44 (9H, 9s).
2-[2-(2-アミノエトキシ)エトキシ]-N,N-ジメチルエタンアミンの製造 Reference Example 71
Preparation of 2- [2- (2-aminoethoxy) ethoxy] -N, N-dimethylethanamine
1H NMR (400 MHz, CDCl3) δ 3.63-3.60 (4H, m), 3.58 (2H, t, J = 5.6 Hz), 3.51 (2H, t, J = 5.2 Hz), 2.87-2.86 (2H, m), 2.52 (2H, t, J = 5.6 Hz), 2.26 (s, 6H). To a solution of tert-butyl (2- {2- [2- (dimethylamino) ethoxy] ethoxy} ethyl) carbamate (236 mg, 0.85 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.5 mL, 14.7 mmol). In addition, after stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol and made basic with 3N aqueous sodium hydroxide. This solution was extracted with dichloromethane / methanol (v / v) = 10/1, and the organic layer was dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give the title compound (137.2 mg, 91%) Obtained as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 3.63-3.60 (4H, m), 3.58 (2H, t, J = 5.6 Hz), 3.51 (2H, t, J = 5.2 Hz), 2.87-2.86 (2H, m), 2.52 (2H, t, J = 5.6 Hz), 2.26 (s, 6H).
1-(2-{2-[2-(ジメチルアミノ)エトキシ]エトキシ}エチル)-3-(4-エチニルフェニル)ウレアの製造 Reference Example 72
Preparation of 1- (2- {2- [2- (dimethylamino) ethoxy] ethoxy} ethyl) -3- (4-ethynylphenyl) urea
1H NMR (400 MHz, CDCl3) δ 9.17 (1H, br s), 7.55 (2H, br d, J = 8.4 Hz), 7.35 (2H, br d, J = 8.4 Hz), 6.70 (1H, br t, J = 4.8 Hz), 4.01-3.99 (2H, m), 3.68-3.66 (2H, m), 3.63-3.61 (2H, m), 3.58 (2H, br t, J = 4.8 Hz), 3.47-3.43 (2H, m), 3.27-3.25 (2H, m), 2.99 (1H, s), 2.88 (6H, s). Add 4-nitrophenyl chloroformate (516 mg, 2.6 mmol), dichloromethane (25 mL), 4-ethynylaniline (300 mg, 2.6 mmol), and pyridine (206 μL, 2.6 mmol), and stir at room temperature for 3 hours The solvent was distilled off under reduced pressure. To a solution of the obtained crude product in dichloromethane (4 mL), 2- [2- (2-aminoethoxy) ethoxy] -N, N-dimethylethanamine (600 mg, 3.4 mmol) in dichloromethane (25 mL) And triethylamine (356.8 μL, 2.6 mmol) were added, and the mixture was stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99/1 → 90/10) to give the title compound (201 mg, 26%) as a white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 9.17 (1H, br s), 7.55 (2H, br d, J = 8.4 Hz), 7.35 (2H, br d, J = 8.4 Hz), 6.70 (1H, br t, J = 4.8 Hz), 4.01-3.99 (2H, m), 3.68-3.66 (2H, m), 3.63-3.61 (2H, m), 3.58 (2H, br t, J = 4.8 Hz), 3.47- 3.43 (2H, m), 3.27-3.25 (2H, m), 2.99 (1H, s), 2.88 (6H, s).
N-[2-(2-{2-[3-(4-エチニルフェニル)ウレイド]エトキシ}エトキシ)エチル]アセトアミドの製造 Reference Example 73
Preparation of N- [2- (2- {2- [3- (4-ethynylphenyl) ureido] ethoxy} ethoxy) ethyl] acetamide
1H NMR (400 MHz, CDCl3) δ 8.51 (1H, br s), 7.43 (2H, br d, J = 8.8 Hz), 7.38 (2H, br d, J = 8.8 Hz), 5.94 (1H, br s), 5.69 (1H, br s), 3.68-3.55 (8H, m), 3.49-3.46 (4H, m), 2.99 (1H, s), 2.04 (3H, s). Acetic anhydride (48.2 μL, 0.51) in 1- {2- [2- (2-aminoethoxy) ethoxy] ethyl} -3- (4-ethynylphenyl) urea (100 mg, 0.34 mmol) in acetonitrile (2 mL) mmol) and 4-dimethylaminopyridine (8.3 mg, 0.068 mmol) were added and stirred at room temperature for 8 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 98/2 → 90/10) to give the title compound (75.2 mg, 66%) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ) δ 8.51 (1H, br s), 7.43 (2H, br d, J = 8.8 Hz), 7.38 (2H, br d, J = 8.8 Hz), 5.94 (1H, br s), 5.69 (1H, br s), 3.68-3.55 (8H, m), 3.49-3.46 (4H, m), 2.99 (1H, s), 2.04 (3H, s).
オキシビス(エタン-2,1-ジイル) ビス(4-メチルベンゼンスルホナート) の製造 Reference Example 74
Production of oxybis (ethane-2,1-diyl) bis (4-methylbenzenesulfonate)
1H NMR (400 MHz, CDCl3) δ 7.78 (4H, d, J = 8.4 Hz), 7.35 (4H, d, J = 8.4 Hz), 4.09 (4H, t, J = 4.8 Hz), 3.61 (4H, t, J = 4.8 Hz), 2.45 (6H, s). To a solution of potassium hydroxide (4.23 g, 75.4 mmol) in dichloromethane (20 mL) was added diethylene glycol (980 μL, 9.4 mmol) and p-toluenesulfonyl chloride (3.58 g, 18.8 mmol) at 0 ° C. Stir for hours. The solution was diluted with water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.38 g, 87%) as a white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (4H, d, J = 8.4 Hz), 7.35 (4H, d, J = 8.4 Hz), 4.09 (4H, t, J = 4.8 Hz), 3.61 (4H , t, J = 4.8 Hz), 2.45 (6H, s).
1-(4-エチニルフェニル)-3-{2-[2-(2-モルホリノエトキシ)エトキシ]エチル}ウレアの製造 Reference Example 75
Preparation of 1- (4-ethynylphenyl) -3- {2- [2- (2-morpholinoethoxy) ethoxy] ethyl} urea
1H NMR (400 MHz, CDCl3) δ 7.89 (1H, br s), 7.38 (2H, br d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 5.90 (1H, br s), 3.71-3.69 (4H, m), 3.62-3.60 (6H, m), 3.55 (2H, t, J = 4.4 Hz), 3.42-3.41 (2H, m), 3.01 (1H, s), 2.62-2.60 (2H, m), 2.53-2.52 (4H, m). To a solution of 1- {2- [2- (2-aminoethoxy) ethoxy] ethyl} -3- (4-ethynylphenyl) urea (136 mg, 0.47 mmol) in acetonitrile (5 mL) was added oxybis (ethane-2, 1-Diyl) bis (4-methylbenzenesulfonate) (233.8 mg, 0.56 mmol) and potassium carbonate (97.4 mg, 0.71 mmol) were added, and the mixture was stirred for 16 hours under reflux with heating, and then the solvent was distilled off under reduced pressure. . Water was added to the residue, and the mixture was extracted with a dichloromethane / methanol (v / v) = 10/1 solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99/1 → 90/10) to give the title compound (116.1 mg, 68%) as a colorless oil.
1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (1H, br s), 7.38 (2H, br d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 5.90 (1H, br s ), 3.71-3.69 (4H, m), 3.62-3.60 (6H, m), 3.55 (2H, t, J = 4.4 Hz), 3.42-3.41 (2H, m), 3.01 (1H, s), 2.62- 2.60 (2H, m), 2.53-2.52 (4H, m).
2-{[3-({3-[3-(2-メトキシエチル)ウレイド]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物1)の製造 Example 1
Preparation of 2-{[3-({3- [3- (2-methoxyethyl) ureido] phenyl} ethynyl) -1H-indazol-6-yl] thio} -N-methylbenzamide (Compound 1)
1H NMR (400 MHz, CD3OD) δ 7.78 (1H, br d, J = 8.4 Hz), 7.69 (1H, t, J = 1.6 Hz), 7.59 (1H, br s), 7.48-7.46 (1H, m), 7.40-7.19 (7H, m), 3.49 (2H, t, J = 5.6 Hz), 3.40-3.37 (5H, m), 2.85 (3H, s). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (3-ethynylphenyl) -3- (2-methoxyethyl) urea ( 63.3 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), and CuI (4.6 mg, 0.024 mmol) in N, N-dimethylformamide (2 mL) in N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) was added at room temperature and stirred for 5 minutes, and then stirred at 80 ° C. for 2 hours. The solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 95/5 → 90/10) to give the title compound (74.3 mg, 61%) as a brown powder.
1 H NMR (400 MHz, CD 3 OD) δ 7.78 (1H, br d, J = 8.4 Hz), 7.69 (1H, t, J = 1.6 Hz), 7.59 (1H, br s), 7.48-7.46 (1H , m), 7.40-7.19 (7H, m), 3.49 (2H, t, J = 5.6 Hz), 3.40-3.37 (5H, m), 2.85 (3H, s).
2-({3-[(3-{3-[2-(2-メトキシエトキシ)エチル]ウレイド}フェニル)エチニル]-1H-インダゾール-6-イル}チオ)-N-メチルベンズアミド(化合物2)の製造 Example 2
2-({3-[(3- {3- [2- (2-methoxyethoxy) ethyl] ureido} phenyl) ethynyl] -1H-indazol-6-yl} thio) -N-methylbenzamide (compound 2) Manufacturing of
1H NMR (400 MHz, DMSO-d6) δ 13.55 (1H, br s), 8.73 (1H, br s), 8.36 (1H, br q, J = 4.8 Hz), 7.81 (1H, br d, J = 8.4 Hz), 7.78 (1H, br s), 7.61 (1H, br s), 7.49 (1H, dd, J = 7.6, 2.0 Hz), 7.37-7.27 (4H, m), 7.21-7.17 (2H, m), 7.05 (1H, br dd, J = 7.6, 2.0 Hz), 6.25 (1H, br t, J = 5.2 Hz), 3.56-3.53 (2H, m), 3.48-3.45 (4H, m), 3.28-3.24 (5H, m), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (3-ethynylphenyl) -3- [2- (2-methoxyethoxy ) Ethyl] urea (76.1 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and N, Using N-diisopropylethylamine (0.13 mL, 0.72 mmol) as a starting material, the title compound (72.6 mg, 55%) was obtained as a pale orange powder by operating in the same manner as in Example 1.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.55 (1H, br s), 8.73 (1H, br s), 8.36 (1H, br q, J = 4.8 Hz), 7.81 (1H, br d, J = 8.4 Hz), 7.78 (1H, br s), 7.61 (1H, br s), 7.49 (1H, dd, J = 7.6, 2.0 Hz), 7.37-7.27 (4H, m), 7.21-7.17 (2H, m), 7.05 (1H, br dd, J = 7.6, 2.0 Hz), 6.25 (1H, br t, J = 5.2 Hz), 3.56-3.53 (2H, m), 3.48-3.45 (4H, m), 3.28 -3.24 (5H, m), 2.76 (3H, d, J = 4.8 Hz).
2-[(3-{[3-(3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレイド)フェニル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物3)の製造 Example 3
2-[(3-{[3- (3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} ureido) phenyl] ethynyl} -1H-indazol-6-yl) thio] -N-methyl Production of benzamide (compound 3)
1H NMR (400 MHz, DMSO-d6) δ 13.55 (1H, br s), 8.72 (1H, br s), 8.35 (1H, br q, J = 4.8 Hz), 7.81 (1H, br d, J = 8.4 Hz), 7.78 (1H, br s), 7.61 (1H, br s), 7.49 (1H, dd, J = 7.6, 2.0 Hz), 7.37-7.27 (4H, m), 7.21-7.17 (2H, m), 7.05 (1H, dd, J = 7.6, 2.0 Hz), 6.25 (1H, br t, J = 5.2 Hz), 3.54-3.51 (6H, m), 3.47-3.43 (4H, m), 3.29-3.24 (5H, m), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (3-ethynylphenyl) -3- {2- [2- (2 -Methoxyethoxy) ethoxy] ethyl} urea (88.8 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL ) And N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as raw materials and the same operation as in Example 1 gave the title compound (58.5 mg, 41%) as a white powder.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.55 (1H, br s), 8.72 (1H, br s), 8.35 (1H, br q, J = 4.8 Hz), 7.81 (1H, br d, J = 8.4 Hz), 7.78 (1H, br s), 7.61 (1H, br s), 7.49 (1H, dd, J = 7.6, 2.0 Hz), 7.37-7.27 (4H, m), 7.21-7.17 (2H, m), 7.05 (1H, dd, J = 7.6, 2.0 Hz), 6.25 (1H, br t, J = 5.2 Hz), 3.54-3.51 (6H, m), 3.47-3.43 (4H, m), 3.29- 3.24 (5H, m), 2.76 (3H, d, J = 4.8 Hz).
2-{[3-({3-[3-(2,5,8,11-テトラオキサトリデカン-13-イル)ウレイド]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物4)の製造 Example 4
2-{[3-({3- [3- (2,5,8,11-tetraoxatridecan-13-yl) ureido] phenyl} ethynyl) -1H-indazol-6-yl] thio} -N -Production of methylbenzamide (compound 4)
1H NMR (400 MHz, CD3OD) δ 7.78 (1H, d, J = 8.8 Hz), 7.70 (1H, br s), 7.59 (1H, br s), 7.47 (1H, br d, J = 7.2 Hz), 7.40 (1H, br d, J = 8.0 Hz), 7.35-7.23 (6H, m), 3.65-3.58 (12H, m), 3.54-3.51 (2H, m), 3.39 (2H, t, J = 5.2 Hz), 3.33 (3H, s), 2.85 (3H, s). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (3-ethynylphenyl) -3- (2,5,8,11 -Tetraoxatridecan-13-yl) urea (102.6 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide ( 2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) were used as raw materials and the same operation as in Example 1 was performed to obtain the title compound (29.5 mg, 19%) as a pale yellow solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.78 (1H, d, J = 8.8 Hz), 7.70 (1H, br s), 7.59 (1H, br s), 7.47 (1H, br d, J = 7.2 Hz), 7.40 (1H, br d, J = 8.0 Hz), 7.35-7.23 (6H, m), 3.65-3.58 (12H, m), 3.54-3.51 (2H, m), 3.39 (2H, t, J = 5.2 Hz), 3.33 (3H, s), 2.85 (3H, s).
2-{[3-({3-[3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレイド]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物5)の製造 Example 5
2-{[3-({3- [3- (2,5,8,11,14-pentaoxahexadecan-16-yl) ureido] phenyl} ethynyl) -1H-indazol-6-yl] thio}- Production of N-methylbenzamide (compound 5)
1H NMR (400 MHz, CDCl3) δ 10.48 (1H, br s), 7.83 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.69 (1H, br s), 7.65-7.63 (1H, m), 7.56 (1H, dt, J = 8.0, 1.8 Hz), 7.51 (1H, br s), 7.32-7.19 (6H, m), 6.34 (1H, br m), 6.02 (1H, br s), 3.77-3.74 (4H, m), 3.70-3.63 (6H, m), 3.61-3.59 (6H, m), 3.50-3.44 (4H, m), 3.27 (3H, s), 2.95 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (150.0 mg, 0.37 mmol), 1- (3-ethynylphenyl) -3- (2,5,8,11 , 14-Pentaoxahexadecan-16-yl) urea (173.0 mg, 0.44 mmol), PdCl 2 (PPh 3 ) 2 (13.0 mg, 0.019 mmol), CuI (6.9 mg, 0.036 mmol), N, N-dimethylformamide (2 mL) and N, N-diisopropylethylamine (0.19 mL, 1.1 mmol) were used as starting materials and were treated in the same manner as in Example 1 to obtain the title compound (43.6 mg, 18%) as a pale yellow solid. .
1 H NMR (400 MHz, CDCl 3 ) δ 10.48 (1H, br s), 7.83 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.69 (1H, br s), 7.65-7.63 (1H, m), 7.56 (1H, dt, J = 8.0, 1.8 Hz), 7.51 (1H, br s), 7.32-7.19 (6H, m), 6.34 (1H, br m), 6.02 (1H, br s), 3.77-3.74 (4H, m), 3.70-3.63 (6H, m), 3.61-3.59 (6H, m), 3.50-3.44 (4H, m), 3.27 (3H, s), 2.95 (3H, d, J = 4.8 Hz).
2-{[3-({4-[3-(2-メトキシエチル)ウレイド]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物6)の製造 Example 6
Preparation of 2-{[3-({4- [3- (2-methoxyethyl) ureido] phenyl} ethynyl) -1H-indazol-6-yl] thio} -N-methylbenzamide (Compound 6)
1H NMR (400 MHz, DMSO-d6) δ 13.46 (1H, br s), 8.82 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.8 Hz), 7.60 (1H, br s), 7.51 (2H, br d, J = 8.8 Hz), 7.49-7.46 (3H, m), 7.32 (1H, td, J = 7.2, 1.6 Hz), 7.29 (1H, td, J = 7.2, 1.6 Hz), 7.18 (1H, dd, J = 8.8, 1.6 Hz), 7.05 (1H, dd, J = 7.2, 1.6 Hz), 6.30 (1H, t, J = 5.6 Hz), 3.39 (2H, t, J = 5.6 Hz), 3.29 (3H, s), 3.26 (2H, m), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (104.6 mg, 0.26 mmol), 1- (4-ethynylphenyl) -3- (2-methoxyethyl) urea ( 108.5 mg, 0.50 mmol), PdCl 2 (PPh 3 ) 2 (5.8 mg, 0.0083 mmol), CuI (2.7 mg, 0.014 mmol), N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine ( The title compound (77.8 mg, 61%) was obtained as a white powder in the same manner as in Example 1, using 0.15 mL, 0.86 mmol) as a starting material.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.46 (1H, br s), 8.82 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.8 Hz ), 7.60 (1H, br s), 7.51 (2H, br d, J = 8.8 Hz), 7.49-7.46 (3H, m), 7.32 (1H, td, J = 7.2, 1.6 Hz), 7.29 (1H, td, J = 7.2, 1.6 Hz), 7.18 (1H, dd, J = 8.8, 1.6 Hz), 7.05 (1H, dd, J = 7.2, 1.6 Hz), 6.30 (1H, t, J = 5.6 Hz), 3.39 (2H, t, J = 5.6 Hz), 3.29 (3H, s), 3.26 (2H, m), 2.76 (3H, d, J = 4.8 Hz).
2-({3-[(4-{3-[2-(2-メトキシエトキシ)エチル]ウレイド}フェニル)エチニル]-1H-インダゾール-6-イル}チオ)-N-メチルベンズアミド(化合物7)の製造 Example 7
2-({3-[(4- {3- [2- (2-methoxyethoxy) ethyl] ureido} phenyl) ethynyl] -1H-indazol-6-yl} thio) -N-methylbenzamide (Compound 7) Manufacturing of
1H NMR (400 MHz, DMSO-d6) δ 13.47 (1H, br s), 8.86 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.60 (1H, br s), 7.53-7.44 (5H, m), 7.32 (1H, td, J = 7.6, 1.2 H), 7.29 (1H, td, J = 7.6, 1.2 Hz), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.2 Hz), 6.29 (1H, t, J = 5.6 Hz), 3.56-3.54 (2H, m), 3.48-3.45 (4H, m), 3.27 (2H, m), 3.26 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (102.5 mg, 0.25 mmol), 1- (4-ethynylphenyl) -3- [2- (2-methoxyethoxy ) Ethyl] urea (132.5 mg, 0.51 mmol), PdCl 2 (PPh 3 ) 2 (5.3 mg, 0.0076 mmol), CuI (3.1 mg, 0.016 mmol), N, N-dimethylformamide (0.8 mL), and N, Using N-diisopropylethylamine (0.15 mL, 0.86 mmol) as a starting material, the title compound (51.2 mg, 38%) was obtained as a white powder in the same manner as in Example 1.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.47 (1H, br s), 8.86 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz ), 7.60 (1H, br s), 7.53-7.44 (5H, m), 7.32 (1H, td, J = 7.6, 1.2 H), 7.29 (1H, td, J = 7.6, 1.2 Hz), 7.18 (1H , dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.2 Hz), 6.29 (1H, t, J = 5.6 Hz), 3.56-3.54 (2H, m), 3.48-3.45 ( 4H, m), 3.27 (2H, m), 3.26 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
2-[(3-{[4-(3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレイド)フェニル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物8)の製造 Example 8
2-[(3-{[4- (3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} ureido) phenyl] ethynyl} -1H-indazol-6-yl) thio] -N-methyl Production of benzamide (compound 8)
融点: 95-96℃
1H NMR (400 MHz, DMSO-d6) δ 13.46 (1H, br s), 8.83 (1H, s), 8.36 (1H, br q, J = 4.4 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.60 (1H, br s), 7.52-7.47 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 6.28 (1H, t, J = 5.6 Hz), 3.54-3.52 (6H, m), 3.47 (2H, t, J = 5.6 Hz), 3.45-3.42 (2H, m), 3.26 (2H, m), 3.24 (3H, s), 2.76 (3H, d, J = 4.4 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (104.4 mg, 0.26 mmol), 1- (4-ethynylphenyl) -3- {2- [2- (2 -Methoxyethoxy) ethoxy] ethyl} urea (118.6 mg, 0.39 mmol), PdCl 2 (PPh 3 ) 2 (5.6 mg, 0.0080 mmol), CuI (3.0 mg, 0.016 mmol), N, N-dimethylformamide (0.8 mL ) And N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) as starting materials, the same operation as in Example 1 was performed to obtain the title compound (49.9 mg, 33%) as a white powder.
Melting point: 95-96 ℃
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.46 (1H, br s), 8.83 (1H, s), 8.36 (1H, br q, J = 4.4 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.60 (1H, br s), 7.52-7.47 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.18 ( 1H, dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 6.28 (1H, t, J = 5.6 Hz), 3.54-3.52 (6H, m), 3.47 (2H , t, J = 5.6 Hz), 3.45-3.42 (2H, m), 3.26 (2H, m), 3.24 (3H, s), 2.76 (3H, d, J = 4.4 Hz).
2-{[3-({4-[3-(2,5,8,11-テトラオキサトリデカン-13-イル)ウレイド]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物9)の製造 Example 9
2-{[3-({4- [3- (2,5,8,11-tetraoxatridecan-13-yl) ureido] phenyl} ethynyl) -1H-indazol-6-yl] thio} -N -Production of methylbenzamide (compound 9)
1H NMR (400 MHz, DMSO-d6) δ 13.46 (1H, br s), 8.83 (1H, s), 8.36 (1H, q, J = 4.4 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.60 (1H, br s), 7.53-7.47 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.27 (1H, td, J = 7.6, 1.6 Hz), 7.17 (1H, dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 6.28 (1H, t, J = 5.6 Hz), 3.55-3.50 (10H, m), 3.47 (2H, br t, J = 5.6 Hz), 3.43-3.41 (2H, m), 3.26 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.4 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (103.8 mg, 0.25 mmol), 1- (4-ethynylphenyl) -3- (2,5,8,11 -Tetraoxatridecan-13-yl) urea (125.3 mg, 0.32 mmol), PdCl 2 (PPh 3 ) 2 (5.6 mg, 0.0080 mmol), CuI (2.8 mg, 0.015 mmol), N, N-dimethylformamide ( 0.8 mL) and N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) were used as raw materials and the same operation as in Example 1 was performed to obtain the title compound (54.8 mg, 34%) as a pale yellow solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.46 (1H, br s), 8.83 (1H, s), 8.36 (1H, q, J = 4.4 Hz), 7.82 (1H, d, J = 8.4 Hz ), 7.60 (1H, br s), 7.53-7.47 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.27 (1H, td, J = 7.6, 1.6 Hz), 7.17 (1H , dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 6.28 (1H, t, J = 5.6 Hz), 3.55-3.50 (10H, m), 3.47 (2H, br t, J = 5.6 Hz), 3.43-3.41 (2H, m), 3.26 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.4 Hz).
2-{[3-({4-[3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレイド]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物10)の製造 Example 10
2-{[3-({4- [3- (2,5,8,11,14-pentaoxahexadecan-16-yl) ureido] phenyl} ethynyl) -1H-indazol-6-yl] thio}- Production of N-methylbenzamide (Compound 10)
1H NMR (400 MHz, DMSO-d6) δ 13.46 (1H, br s), 8.83 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.60 (1H, br s), 7.52-7.47 (5H, m), 7.31 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 6.28 (1H, t, J = 5.6 Hz), 3.55-3.45 (16H, m), 3.43-3.41 (2H, m), 3.27 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (101.7 mg, 0.25 mmol), 1- (4-ethynylphenyl) -3- (2,5,8,11 , 14-pentaoxahexadecan-16-yl) urea (114.4 mg, 0.33 mmol), PdCl 2 (PPh 3 ) 2 (5.8 mg, 0.0083 mmol), CuI (2.8 mg, 0.015 mmol), N, N-dimethylformamide (0.8 mL) and N, N-diisopropylamine (0.15 mL, 0.86 mmol) were used as starting materials and the same operation as in Example 1 was performed to obtain the title compound (48.2 mg, 29%) as an orange solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.46 (1H, br s), 8.83 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz ), 7.60 (1H, br s), 7.52-7.47 (5H, m), 7.31 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.18 (1H , dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 6.28 (1H, t, J = 5.6 Hz), 3.55-3.45 (16H, m), 3.43-3.41 ( 2H, m), 3.27 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
2-メトキシエチル {3-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}カルバメート(化合物11)の製造 Example 11
Preparation of 2-methoxyethyl {3-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} carbamate (Compound 11)
1H NMR (400 MHz, CDCl3) δ 11.39 (1H, br s), 7.85 (1H, br s), 7.78 (1H, d, J = 8.4 Hz), 7.69-7.53 (5H, m), 7.48-7.46 (1H, m), 7.31-7.25 (2H, m), 7.21-7.17 (2H, m), 6.35 (1H, br q, J = 4.8 Hz), 4.36 (2H, br t, J = 4.4 Hz), 3.69 (2H, br t, J = 4.4 Hz), 3.44 (3H, s), 2.96 (3H, br d, J = 4.8 Hz). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 2-methoxyethyl (3-ethynylphenyl) carbamate (63.6 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol). The title compound (72.8 mg, 60%) was obtained as a white powder by using in the same manner as in Example 1, using as a raw material.
1 H NMR (400 MHz, CDCl 3 ) δ 11.39 (1H, br s), 7.85 (1H, br s), 7.78 (1H, d, J = 8.4 Hz), 7.69-7.53 (5H, m), 7.48- 7.46 (1H, m), 7.31-7.25 (2H, m), 7.21-7.17 (2H, m), 6.35 (1H, br q, J = 4.8 Hz), 4.36 (2H, br t, J = 4.4 Hz) , 3.69 (2H, br t, J = 4.4 Hz), 3.44 (3H, s), 2.96 (3H, br d, J = 4.8 Hz).
2-(2-メトキシエトキシ)エチル {3-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}カルバメート(化合物12)の製造 Example 12
Preparation of 2- (2-methoxyethoxy) ethyl {3-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} carbamate (Compound 12)
1H NMR (400 MHz, CDCl3) δ 10.97 (1H, br s), 7.78 (1H, d, J = 8.4 Hz), 7.64-7.52 (5H, m), 7.31-7.18 (6H, m), 6.33 (1H, br m), 4.34 (2H, br t, J = 4.4 Hz), 3.78 (2H, br t, J = 4.4 Hz), 3.72-3.69 (2H, m), 3.59-3.57 (2H, m), 3.36 (3H, s), 2.96 (3H, br d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 2- (2-methoxyethoxy) ethyl (3-ethynylphenyl) carbamate (76.4 mg , 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (0.13 mL) , 0.72 mmol) as a starting material, and the same operation as in Example 1 yielded the title compound (70.1 mg, 53%) as a white powder.
1 H NMR (400 MHz, CDCl 3 ) δ 10.97 (1H, br s), 7.78 (1H, d, J = 8.4 Hz), 7.64-7.52 (5H, m), 7.31-7.18 (6H, m), 6.33 (1H, br m), 4.34 (2H, br t, J = 4.4 Hz), 3.78 (2H, br t, J = 4.4 Hz), 3.72-3.69 (2H, m), 3.59-3.57 (2H, m) , 3.36 (3H, s), 2.96 (3H, br d, J = 4.8 Hz).
2-[2-(2-メトキシエトキシ)エトキシ]エチル {3-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}カルバメート(化合物13)の製造 Example 13
2- [2- (2-methoxyethoxy) ethoxy] ethyl {3-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} carbamate (compound 13 )Manufacturing of
1H NMR (400 MHz, CDCl3) δ 11.62 (1H, br s), 7.97 (1H, br s), 7.75 (1H, br d, J = 8.4 Hz), 7.62-7.59 (4H, m), 7.28-7.16 (6H, m), 6.43 (1H, br m), 4.31 (2H, br t, J = 4.4 Hz), 3.76 (2H, br t, J = 4.4 Hz), 3.72-3.70 (2H, m), 3.68-3.66 (2H, m), 3.62-3.60 (2H, m), 3.49-3.47 (2H, m), 3.29 (3H, s), 2.96 (3H, br d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 2- [2- (2-methoxyethoxy) ethoxy] ethyl (3-ethynylphenyl ) Carbamate (89.1 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and N, N- Using diisopropylethylamine (0.13 mL, 0.72 mmol) as a starting material, the title compound (57.7 mg, 40%) was obtained as a pale yellow powder in the same manner as in Example 1.
1 H NMR (400 MHz, CDCl 3 ) δ 11.62 (1H, br s), 7.97 (1H, br s), 7.75 (1H, br d, J = 8.4 Hz), 7.62-7.59 (4H, m), 7.28 -7.16 (6H, m), 6.43 (1H, br m), 4.31 (2H, br t, J = 4.4 Hz), 3.76 (2H, br t, J = 4.4 Hz), 3.72-3.70 (2H, m) , 3.68-3.66 (2H, m), 3.62-3.60 (2H, m), 3.49-3.47 (2H, m), 3.29 (3H, s), 2.96 (3H, br d, J = 4.8 Hz).
2-メトキシエチル {4-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}カルバメート(化合物14)の製造 Example 14
Preparation of 2-methoxyethyl {4-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} carbamate (Compound 14)
1H NMR (400 MHz, DMSO-d6) δ 13.49 (1H, br s), 10.02 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.60-7.55 (5H, m), 7.49-7.48 (1H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 4.23 (2H, br t, J = 4.8 Hz), 3.58 (2H, br t, J = 4.8 Hz), 3.29 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (101.2 mg, 0.25 mmol), 2-methoxyethyl (4-ethynylphenyl) carbamate (88.8 mg, 0.41 mmol), PdCl 2 (PPh 3 ) 2 (5.9 mg, 0.0084 mmol), CuI (2.7 mg, 0.014 mmol), N, N-dimethylformamide (0.8 mL), and N, N-diisopropylethylamine (0.15 mL, 0.86 mmol). The title compound (69.8 mg, 56%) was obtained as a pale yellow powder by operating in the same manner as in Example 1 using the starting material.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.49 (1H, br s), 10.02 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz ), 7.60-7.55 (5H, m), 7.49-7.48 (1H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.18 ( 1H, dd, J = 8.4, 1.6 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 4.23 (2H, br t, J = 4.8 Hz), 3.58 (2H, br t, J = 4.8 Hz) ), 3.29 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
2-(2-メトキシエトキシ)エチル {4-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}カルバメート(化合物15)の製造 Example 15
Preparation of 2- (2-methoxyethoxy) ethyl {4-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} carbamate (Compound 15)
1H NMR (400 MHz, DMSO-d6) δ 13.48 (1H, br s), 10.01 (1H, s), 8.35 (1H, q, J = 4.4 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.59-7.54 (5H, m), 7.49-7.46 (1H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.27 (1H, td, J = 7.6, 1.6 Hz), 7.17 (1H, dd, J = 8.4, 1.2 Hz), 7.04 (1H, dd, J = 7.6, 1.6 Hz), 4.22 (2H, br t, J = 4.8 Hz), 3.65 (2H, br t, J = 4.8 Hz), 3.57-3.54 (2H, m), 3.46-3.43 (2H, m), 3.24 (3H, s), 2.75 (3H, d, J = 4.4 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (101.2 mg, 0.25 mmol), 2- (2-methoxyethoxy) ethyl (4-ethynylphenyl) carbamate (102.4 mg , 0.39 mmol), PdCl 2 (PPh 3 ) 2 (5.3 mg, 0.0076 mmol), CuI (2.8 mg, 0.015 mmol), N, N-dimethylformamide (1.0 mL), and N, N-diisopropylethylamine (0.15 mL) , 0.86 mmol) as a starting material and the same operation as in Example 1 yielded the title compound (79.4 mg, 59%) as a white powder.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.48 (1H, br s), 10.01 (1H, s), 8.35 (1H, q, J = 4.4 Hz), 7.81 (1H, d, J = 8.4 Hz ), 7.59-7.54 (5H, m), 7.49-7.46 (1H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.27 (1H, td, J = 7.6, 1.6 Hz), 7.17 ( 1H, dd, J = 8.4, 1.2 Hz), 7.04 (1H, dd, J = 7.6, 1.6 Hz), 4.22 (2H, br t, J = 4.8 Hz), 3.65 (2H, br t, J = 4.8 Hz) ), 3.57-3.54 (2H, m), 3.46-3.43 (2H, m), 3.24 (3H, s), 2.75 (3H, d, J = 4.4 Hz).
2-[2-(2-メトキシエトキシ)エトキシ]エチル {4-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}カルバメート(化合物16)の製造 Example 16
2- [2- (2-methoxyethoxy) ethoxy] ethyl {4-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} carbamate (compound 16 )Manufacturing of
融点: 103-104℃
1H NMR (400 MHz, DMSO-d6) δ 13.48 (1H, br s), 10.02 (1H, s), 8.35 (1H, q, J = 4.8 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.59 (1H, br s), 7.56 (4H, br m), 7.48 (1H, dd, J = 7.6, 1.6 Hz), 7.31 (1H, td, J = 7.6, 1.6 Hz), 7.27 (1H, td, J = 7.6. 1.6 Hz), 7.17 (1H, dd, J = 8.4, 1.2 Hz), 7.04 (1H, dd, J = 7.6, 1.6 Hz), 4.22 (2H, br t, J = 4.4 Hz), 3.65 (2H, br t, J = 4.4 Hz), 3.57-3.49 (6H, m), 3.42-3.39 (2H, m), 3.22 (3H, s), 2.75 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (101.5 mg, 0.25 mmol), 2- [2- (2-methoxyethoxy) ethoxy] ethyl (4-ethynylphenyl) ) Carbamate (122.7 mg, 0.40 mmol), PdCl 2 (PPh 3 ) 2 (5.7 mg, 0.0081 mmol), CuI (2.9 mg, 0.015 mmol), N, N-dimethylformamide (1.0 mL), and N, N- Using diisopropylethylamine (0.15 mL, 0.86 mmol) as a starting material, the title compound (90.9 mg, 62%) was obtained as a white powder in the same manner as in Example 1.
Melting point: 103-104 ℃
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.48 (1H, br s), 10.02 (1H, s), 8.35 (1H, q, J = 4.8 Hz), 7.81 (1H, d, J = 8.4 Hz ), 7.59 (1H, br s), 7.56 (4H, br m), 7.48 (1H, dd, J = 7.6, 1.6 Hz), 7.31 (1H, td, J = 7.6, 1.6 Hz), 7.27 (1H, td, J = 7.6.1.6 Hz), 7.17 (1H, dd, J = 8.4, 1.2 Hz), 7.04 (1H, dd, J = 7.6, 1.6 Hz), 4.22 (2H, br t, J = 4.4 Hz) , 3.65 (2H, br t, J = 4.4 Hz), 3.57-3.49 (6H, m), 3.42-3.39 (2H, m), 3.22 (3H, s), 2.75 (3H, d, J = 4.8 Hz) .
2,5,8,11-テトラオキサトリデカン-13-イル {4-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}カルバメート(化合物17)の製造 Example 17
2,5,8,11-tetraoxatridecan-13-yl {4-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} carbamate ( Production of compound 17)
1H NMR (400 MHz, DMSO-d6) δ 13.49 (1H, br s), 10.04 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, br d, J = 8.4 Hz), 7.60 (1H, br s), 7.57 (4H, m), 7.50-7.48 (1H, m), 7.35-7.27 (2H, m), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 4.24-4.22 (2H, m), 3.68-3.66 (2H, m), 3.57-3.49 (10H, m), 3.43-3.40 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (103.1 mg, 0.25 mmol), 2,5,8,11-tetraoxatridecan-13-yl (4- Ethynylphenyl) carbamate (129.8 mg, 0.37 mmol), PdCl 2 (PPh 3 ) 2 (5.6 mg, 0.0080 mmol), CuI (3.1 mg, 0.016 mmol), N, N-dimethylformamide (0.8 mL), and N, Using N-diisopropylethylamine (0.15 mL, 0.86 mmol) as a starting material, the title compound (77.6 mg, 48%) was obtained as an orange solid by operating in the same manner as in Example 1.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.49 (1H, br s), 10.04 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, br d, J = 8.4 Hz), 7.60 (1H, br s), 7.57 (4H, m), 7.50-7.48 (1H, m), 7.35-7.27 (2H, m), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 7.05 (1H, dd, J = 7.6, 1.6 Hz), 4.24-4.22 (2H, m), 3.68-3.66 (2H, m), 3.57-3.49 (10H, m), 3.43-3.40 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
2,5,8,11,14-ペンタオキサヘキサデカン-16-イル {4-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}カルバメート(化合物18)の製造 Example 18
2,5,8,11,14-pentaoxahexadecan-16-yl {4-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} carbamate Production of (Compound 18)
1H NMR (400 MHz, DMSO-d6) δ 13.49 (1H, br s), 10.04 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.60 (1H, br s), 7.57 (4H, m), 7.49-7.48 (1H, m), 7.32 (1H, td, J = 7.6, 2.0 Hz), 7.29 (1H, td, J = 7.6, 2.0 Hz), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.05 (1H, dd, J = 7.6, 2.0 Hz), 4.23 (2H, br t, J = 4.4 Hz), 3.67 (2H, br t, J = 4.4 Hz), 3.58-3.48 (14H, m), 3.43-3.40 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (107.0 mg, 0.26 mmol), 2,5,8,11,14-pentaoxahexadecan-16-yl (4 -Ethynylphenyl) carbamate (160.4 mg, 0.41 mmol), PdCl 2 (PPh 3 ) 2 (5.2 mg, 0.0074 mmol), CuI (3.1 mg, 0.016 mmol), N, N-dimethylformamide (0.8 mL), and N , N-diisopropylethylamine (0.15 mL, 0.86 mmol) was used in the same manner as in Example 1 to obtain the title compound (77.9 mg, 44%) as an orange solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.49 (1H, br s), 10.04 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz ), 7.60 (1H, br s), 7.57 (4H, m), 7.49-7.48 (1H, m), 7.32 (1H, td, J = 7.6, 2.0 Hz), 7.29 (1H, td, J = 7.6, 2.0 Hz), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.05 (1H, dd, J = 7.6, 2.0 Hz), 4.23 (2H, br t, J = 4.4 Hz), 3.67 (2H, br t, J = 4.4 Hz), 3.58-3.48 (14H, m), 3.43-3.40 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
N-{3-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}-2,5,8,11,14,17-ヘキサオキサノナデカン-19-アミド(化合物19)の製造 Example 19
N- {3-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} -2,5,8,11,14,17-hexaoxanona Production of decane-19-amide (compound 19)
1H NMR (400 MHz, DMSO-d6) δ 13.58 (1H, br s), 9.77 (1H, s), 8.37 (1H, q, J = 4.4 Hz), 7.99 (1H, br t, J = 1.6 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.70 (1H, dt, J = 7.6, 1.6 Hz), 7.62 (1H, br s), 7.50-7.48 (1H, m), 7.42 (1H, t, J = 7.6 Hz), 7.38 (1H, dt, J = 7.6, 1.6 Hz), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.20 (1H, dd, J = 8.4, 1.6 Hz), 7.07-7.05 (1H, m), 4.11 (2H, s), 3.70-3.68 (2H, m), 3.64-3.62 (2H, m), 3.58-3.54 (4H, m), 3.51-3.47 (10H, m), 3.41-3.39 (2H, m), 3.22 (3H, s), 2.76 (3H, d, J = 4.4 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.5 mg, 0.25 mmol), PdCl 2 (PPh 3 ) 2 (5.2 mg, 0.0074 mmol), CuI (2.6 mg , 0.014 mmol), N, N-dimethylformamide (1.7 mL), N- (3-ethynylphenyl) -2,5,8,11,14,17-hexaoxanonadecane-19-amide (140.1 mg, 0.34 mmol) and N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) as raw materials and the same operation as in Example 1 gave the title compound (33.0 mg, 19%) as an orange solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.58 (1H, br s), 9.77 (1H, s), 8.37 (1H, q, J = 4.4 Hz), 7.99 (1H, br t, J = 1.6 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.70 (1H, dt, J = 7.6, 1.6 Hz), 7.62 (1H, br s), 7.50-7.48 (1H, m), 7.42 (1H, t, J = 7.6 Hz), 7.38 (1H, dt, J = 7.6, 1.6 Hz), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.20 (1H, dd, J = 8.4, 1.6 Hz), 7.07-7.05 (1H, m), 4.11 (2H, s), 3.70-3.68 (2H, m), 3.64-3.62 (2H, m), 3.58- 3.54 (4H, m), 3.51-3.47 (10H, m), 3.41-3.39 (2H, m), 3.22 (3H, s), 2.76 (3H, d, J = 4.4 Hz).
N-{4-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}-2,5,8,11-テトラオキサトリデカン-13-アミド(化合物20)の製造 Example 20
N- {4-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} -2,5,8,11-tetraoxatridecane-13- Preparation of amide (compound 20)
1H NMR (400 MHz, DMSO-d6) δ 13.50 (1H, s), 9.84 (1H, s), 8.35 (1H, br q, J = 4.4 Hz), 7.83 (1H, d, J = 8.4 Hz), 7.75 (2H, br d, J = 8.8 Hz), 7.61 (2H, br d, J = 8.8 Hz), 7.60 (1H, br s), 7.48 (1H, dd, J = 7.2, 2.0 Hz), 7.34-7.26 (2H, m), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.05 (1H, br d, J = 7.2 Hz), 4.11 (2H, s), 3.70-3.67 (2H, m), 3.63-3.61 (2H, m), 3.57-3.51 (6H, m), 3.43-3.41 (2H, m), 3.23 (3H, s), 2.76 (3H, br d, J = 4.4 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), N- (4-ethynylphenyl) -2,5,8,11-tetraoxa Tridecan-13-amide (93.2 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), acetonitrile (1 mL), and triethylamine (1 mL) Was used in the same manner as in Example 1 to obtain the title compound (91.1 mg, 62%) as an orange solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.50 (1H, s), 9.84 (1H, s), 8.35 (1H, br q, J = 4.4 Hz), 7.83 (1H, d, J = 8.4 Hz ), 7.75 (2H, br d, J = 8.8 Hz), 7.61 (2H, br d, J = 8.8 Hz), 7.60 (1H, br s), 7.48 (1H, dd, J = 7.2, 2.0 Hz), 7.34-7.26 (2H, m), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.05 (1H, br d, J = 7.2 Hz), 4.11 (2H, s), 3.70-3.67 (2H, m ), 3.63-3.61 (2H, m), 3.57-3.51 (6H, m), 3.43-3.41 (2H, m), 3.23 (3H, s), 2.76 (3H, br d, J = 4.4 Hz).
N-{4-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}-2,5,8,11,14-ペンタオキサヘキサデカン-16-アミド(化合物21)の製造 Example 21
N- {4-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} -2,5,8,11,14-pentaoxahexadecane-16 -Amide (compound 21) production
1H NMR (400 MHz, DMSO-d6) δ 13.50 (1H, s), 9.83 (1H, s), 8.35 (1H, br q, J = 4.4 Hz), 7.83 (1H, br d, J = 8.4 Hz), 7.75 (2H, br d, J = 8.8 Hz), 7.61 (2H, br d, J = 8.8 Hz), 7.60 (1H, br s), 7.49 (1H, dd, J = 7.2, 2.0 Hz), 7.34-7.26 (2H, m), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.05 (1H, br d, J = 7.2 Hz), 4.11 (2H, s), 3.70-3.67 (2H, m), 3.64-3.61 (2H, m), 3.57-3.49 (10H, m), 3.42-3.40 (2H, m), 3.22 (3H, s), 2.76 (3H, br d, J = 4.4 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), N- (4-ethynylphenyl) -2,5,8,11,14- Pentaoxahexadecane-16-amide (105.9 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), acetonitrile (1 mL), and triethylamine (1 mL ) As a starting material and was treated in the same manner as in Example 1 to obtain the title compound (75.0 mg, 47%) as an orange solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.50 (1H, s), 9.83 (1H, s), 8.35 (1H, br q, J = 4.4 Hz), 7.83 (1H, br d, J = 8.4 Hz), 7.75 (2H, br d, J = 8.8 Hz), 7.61 (2H, br d, J = 8.8 Hz), 7.60 (1H, br s), 7.49 (1H, dd, J = 7.2, 2.0 Hz) , 7.34-7.26 (2H, m), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.05 (1H, br d, J = 7.2 Hz), 4.11 (2H, s), 3.70-3.67 (2H, m), 3.64-3.61 (2H, m), 3.57-3.49 (10H, m), 3.42-3.40 (2H, m), 3.22 (3H, s), 2.76 (3H, br d, J = 4.4 Hz).
N-{4-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]フェニル}-2,5,8,11,14,17-ヘキサオキサノナデカン-19-アミド(化合物22)の製造 Example 22
N- {4-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] phenyl} -2,5,8,11,14,17-hexaoxanona Production of decane-19-amide (compound 22)
1H NMR (400 MHz, DMSO-d6) δ 13.51 (1H, br s), 9.84 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.83 (1H, d, J = 8.4 Hz), 7.76 (2H, br d, J = 8.8 Hz), 7.62-7.60 (3H, m), 7.50-7.48 (1H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.06-7.04 (1H, m), 4.11 (2H, s), 3.69-3.67 (2H, m), 3.63-3.61 (2H, m), 3.58-3.53 (4H, m), 3.51-3.48 (10H, m), 3.42-3.39 (2H, m), 3.22 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.6 mg, 0.25 mmol), PdCl 2 (PPh 3 ) 2 (5.4 mg, 0.0077 mmol), CuI (2.5 mg , 0.013 mmol), N, N-dimethylformamide (0.8 mL), N- (4-ethynylphenyl) -2,5,8,11,14,17-hexaoxanonadecane-19-amide (142.1 mg, 0.35 mmol) and N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) as raw materials and the same operation as in Example 1 gave the title compound (54.7 mg, 32%) as a light brown solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.51 (1H, br s), 9.84 (1H, s), 8.36 (1H, q, J = 4.8 Hz), 7.83 (1H, d, J = 8.4 Hz ), 7.76 (2H, br d, J = 8.8 Hz), 7.62-7.60 (3H, m), 7.50-7.48 (1H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H , td, J = 7.6, 1.6 Hz), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.06-7.04 (1H, m), 4.11 (2H, s), 3.69-3.67 (2H, m), 3.63-3.61 (2H, m), 3.58-3.53 (4H, m), 3.51-3.48 (10H, m), 3.42-3.39 (2H, m), 3.22 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
2-{[3-({3-[(2-メトキシエチル)アミノ]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物23)の製造 Example 23
Preparation of 2-{[3-({3-[(2-methoxyethyl) amino] phenyl} ethynyl) -1H-indazol-6-yl] thio} -N-methylbenzamide (Compound 23)
1H NMR (400 MHz, CDCl3) δ 10.08 (1H, br s), 7.82 (1H, d, J = 8.4 Hz), 7.66-7.64 (1H, m), 7.48 (1H, br s), 7.33-7.31 (3H, m), 7.22 (1H, dd, J = 8.4, 1.6 H), 7.17 (1H, t, J = 8.0 H), 6.99 (1H, br d, J = 8.0 Hz), 6.88 (1H, t, J = 2.0 Hz), 6.66 (1H, dd, J = 8.0, 2.0 Hz), 6.29 (1H, br m), 4.11 (1H, br m), 3.62 (2H, t, J = 5.6 Hz), 3.40 (3H, s), 3.34-3.33 (2H, m), 2.95 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100 mg, 0.24 mmol), 3-ethynyl-N- (2-methoxyethyl) aniline (50.8 mg, 0.29 mmol) ), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) ) Was used as a starting material in the same manner as in Example 1 to obtain the title compound (15 mg, 10%) as a white powder.
1 H NMR (400 MHz, CDCl 3 ) δ 10.08 (1H, br s), 7.82 (1H, d, J = 8.4 Hz), 7.66-7.64 (1H, m), 7.48 (1H, br s), 7.33- 7.31 (3H, m), 7.22 (1H, dd, J = 8.4, 1.6 H), 7.17 (1H, t, J = 8.0 H), 6.99 (1H, br d, J = 8.0 Hz), 6.88 (1H, t, J = 2.0 Hz), 6.66 (1H, dd, J = 8.0, 2.0 Hz), 6.29 (1H, br m), 4.11 (1H, br m), 3.62 (2H, t, J = 5.6 Hz), 3.40 (3H, s), 3.34-3.33 (2H, m), 2.95 (3H, d, J = 4.8 Hz).
2-({3-[(3-{[2-(2-メトキシエトキシ)エチル]アミノ}フェニル)エチニル]-1H-インダゾール-6-イル}チオ)-N-メチルベンズアミド(化合物24)の製造 Example 24
Preparation of 2-({3-[(3-{[2- (2-methoxyethoxy) ethyl] amino} phenyl) ethynyl] -1H-indazol-6-yl} thio) -N-methylbenzamide (Compound 24)
1H NMR (400 MHz, CDCl3) δ 10.14 (1H, br s), 7.82 (1H, d, J = 8.4 Hz), 7.66-7.64 (1H, m), 7.49 (1H, br s), 7.33-7.30 (3H, m), 7.22 (1H, dd, J = 8.4, 1.2 H), 7.17 (1H, t, J = 8.0 H), 6.98 (1H, d, J = 8.0 Hz), 6.88 (1H, t, J = 2.0 Hz), 6.66 (1H, br d, J = 8.0 Hz), 6.30 (1H, br m), 4.22 (1H, br m), 3.73 (2H, t, J = 5.2 Hz), 3.67-3.65 (2H, m), 3.58-3.56 (2H, m), 3.41 (3H, s), 3.34-3.33 (2H, m), 2.95 (3H, d, J = 5.2 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 3-ethynyl-N- [2- (2-methoxyethoxy) ethyl] aniline ( 64.2 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine ( 0.13 mL, 0.72 mmol) was used as a starting material, and the same operation as in Example 1 was performed to obtain the title compound (51.4 mg, 42%) as a pale yellow powder.
1 H NMR (400 MHz, CDCl 3 ) δ 10.14 (1H, br s), 7.82 (1H, d, J = 8.4 Hz), 7.66-7.64 (1H, m), 7.49 (1H, br s), 7.33- 7.30 (3H, m), 7.22 (1H, dd, J = 8.4, 1.2 H), 7.17 (1H, t, J = 8.0 H), 6.98 (1H, d, J = 8.0 Hz), 6.88 (1H, t , J = 2.0 Hz), 6.66 (1H, br d, J = 8.0 Hz), 6.30 (1H, br m), 4.22 (1H, br m), 3.73 (2H, t, J = 5.2 Hz), 3.67- 3.65 (2H, m), 3.58-3.56 (2H, m), 3.41 (3H, s), 3.34-3.33 (2H, m), 2.95 (3H, d, J = 5.2 Hz).
2-[(3-{[3-({2-[2-(2-メトキシエトキシ)エトキシ]エチル}アミノ)フェニル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物25)の製造 Example 25
2-[(3-{[3-({2- [2- (2-methoxyethoxy) ethoxy] ethyl} amino) phenyl] ethynyl} -1H-indazol-6-yl) thio] -N-methylbenzamide ( Production of compound 25)
1H NMR (400 MHz, CDCl3) δ 10.70 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.63-7.61 (1H, m), 7.59 (1H, br s), 7.29-7.26 (3H, m), 7.22-7.19 (1H, m), 7.16 (1H, t, J = 8.0 Hz), 6.97 (1H, d, J = 8.0 Hz), 6.87 (1H, t, J = 2.0 Hz), 6.65 (1H, dd, J = 8.0, 2.0 Hz), 6.32 (1H, br m), 4.26 (1H, br m), 3.72 (2H, d, J = 5.2 Hz), 3.67-3.66 (6H, m), 3.57-3.55 (2H, m), 3.38 (3H, s), 3.32-3.31 (2H, m), 2.96 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 3-ethynyl-N- {2- [2- (2-methoxyethoxy) ethoxy ] Ethyl} aniline (76.4 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and N, Using N-diisopropylethylamine (0.13 mL, 0.72 mmol) as a starting material, the title compound (47.3 mg, 36%) was obtained as a pale yellow solid in the same manner as in Example 1.
1 H NMR (400 MHz, CDCl 3 ) δ 10.70 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.63-7.61 (1H, m), 7.59 (1H, br s), 7.29- 7.26 (3H, m), 7.22-7.19 (1H, m), 7.16 (1H, t, J = 8.0 Hz), 6.97 (1H, d, J = 8.0 Hz), 6.87 (1H, t, J = 2.0 Hz ), 6.65 (1H, dd, J = 8.0, 2.0 Hz), 6.32 (1H, br m), 4.26 (1H, br m), 3.72 (2H, d, J = 5.2 Hz), 3.67-3.66 (6H, m), 3.57-3.55 (2H, m), 3.38 (3H, s), 3.32-3.31 (2H, m), 2.96 (3H, d, J = 4.8 Hz).
2-({3-[(4-{[2-(2-メトキシエトキシ)エチル]アミノ}フェニル)エチニル]-1H-インダゾール-6-イル}チオ)-N-メチルベンズアミド(化合物26)の製造 Example 26
Preparation of 2-({3-[(4-{[2- (2-methoxyethoxy) ethyl] amino} phenyl) ethynyl] -1H-indazol-6-yl} thio) -N-methylbenzamide (Compound 26)
1H NMR (400 MHz, CDCl3) δ 10.36 (1H, br s), 7.81 (1H, br d, J = 8.4 Hz), 7.64-7.62 (1H, m), 7.52 (1H, br s), 7.44 (2H, br d, J = 8.4 Hz), 7.30-7.28 (2H, m), 7.22-7.18 (2H, m), 6.59 (2H, br d, J = 8.4 Hz), 6.31 (1H, br m), 4.40 (1H, br m), 3.72 (2H, t, J = 5.2 Hz), 3.67-3.65 (2H, m), 3.58-3.56 (2H, m), 3.41 (3H, s), 3.36-3.34 (2H, m), 2.95 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (120.0 mg, 0.29 mmol), 4-ethynyl-N- [2- (2-methoxyethoxy) ethyl] aniline ( 77.0 mg, 0.35 mmol), PdCl 2 (PPh 3 ) 2 (10.3 mg, 0.015 mmol), CuI (5.5 mg, 0.029 mmol), N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine ( The title compound (11.5 mg, 8%) was obtained as a pale yellow powder in the same manner as in Example 1 using 0.15 mL, 0.88 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 10.36 (1H, br s), 7.81 (1H, br d, J = 8.4 Hz), 7.64-7.62 (1H, m), 7.52 (1H, br s), 7.44 (2H, br d, J = 8.4 Hz), 7.30-7.28 (2H, m), 7.22-7.18 (2H, m), 6.59 (2H, br d, J = 8.4 Hz), 6.31 (1H, br m) , 4.40 (1H, br m), 3.72 (2H, t, J = 5.2 Hz), 3.67-3.65 (2H, m), 3.58-3.56 (2H, m), 3.41 (3H, s), 3.36-3.34 ( 2H, m), 2.95 (3H, d, J = 4.8 Hz).
2-[(3-{[4-({2-[2-(2-メトキシエトキシ)エトキシ]エチル}アミノ)フェニル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物27)の製造 Example 27
2-[(3-{[4-({2- [2- (2-methoxyethoxy) ethoxy] ethyl} amino) phenyl] ethynyl} -1H-indazol-6-yl) thio] -N-methylbenzamide ( Production of compound 27)
融点: 66-67℃
1H NMR (400 MHz, CDCl3) δ 10.12 (1H, br s), 7.81 (1H, br d, J = 8.4 Hz), 7.65-7.63 (1H, m), 7.48 (1H, br s), 7.44 (2H, br d, J = 8.8 Hz), 7.32-7.29 (2H, m), 7.24-7.22 (1H, m), 7.20 (1H, dd, J = 8.4, 1.2 Hz), 6.60 (2H, br d, J = 8.8 Hz), 6.30 (1H, br m), 4.44 (1H, br m), 3.72 (2H, t, J = 5.2 Hz), 3.67-3.65 (6H, m), 3.58-3.56 (2H, m), 3.40 (3H, s), 3.35-3.31 (2H, m), 2.95 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 4-ethynyl-N- {2- [2- (2-methoxyethoxy) ethoxy ] Ethyl} aniline (77.0 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and N, Using N-diisopropylethylamine (0.13 mL, 0.72 mmol) as a starting material, the title compound (41.6 mg, 31%) was obtained as a pale yellow solid in the same manner as in Example 1.
Melting point: 66-67 ℃
1 H NMR (400 MHz, CDCl 3 ) δ 10.12 (1H, br s), 7.81 (1H, br d, J = 8.4 Hz), 7.65-7.63 (1H, m), 7.48 (1H, br s), 7.44 (2H, br d, J = 8.8 Hz), 7.32-7.29 (2H, m), 7.24-7.22 (1H, m), 7.20 (1H, dd, J = 8.4, 1.2 Hz), 6.60 (2H, br d , J = 8.8 Hz), 6.30 (1H, br m), 4.44 (1H, br m), 3.72 (2H, t, J = 5.2 Hz), 3.67-3.65 (6H, m), 3.58-3.56 (2H, m), 3.40 (3H, s), 3.35-3.31 (2H, m), 2.95 (3H, d, J = 4.8 Hz).
2-{[3-({4-[(2,5,8,11-テトラオキサトリデカン-13-イル)アミノ]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物28)の製造 Example 28
2-{[3-({4-[(2,5,8,11-tetraoxatridecan-13-yl) amino] phenyl} ethynyl) -1H-indazol-6-yl] thio} -N-methyl Production of benzamide (compound 28)
1H NMR (400 MHz, CDCl3) δ 11.36 (1H, br s), 7.80 (1H, br d, J = 8.4 Hz), 7.68 (1H, br s), 7.59-7.57 (1H, m), 7.42 (2H, br d, J = 8.6 Hz), 7.25-7.22 (2H, m), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 7.13-7.11 (1H, m), 6.57 (2H, br d, J = 8.6 Hz), 6.38 (1H, br m), 4.48 (1H, br m), 3.70 (2H, t, J = 5.2 Hz), 3.68-3.63 (10H, m), 3.55-3.53 (2H, m), 3.36 (3H, s), 3.31 (2H, m), 2.97 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), N- (4-ethynylphenyl) -2,5,8,11-tetraoxa Tridecan-13-amine (100.0 mg, 0.33 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), and Using N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as a starting material, the title compound (25.4 mg, 18%) was obtained as a brown solid in the same manner as in Example 1.
1 H NMR (400 MHz, CDCl 3 ) δ 11.36 (1H, br s), 7.80 (1H, br d, J = 8.4 Hz), 7.68 (1H, br s), 7.59-7.57 (1H, m), 7.42 (2H, br d, J = 8.6 Hz), 7.25-7.22 (2H, m), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 7.13-7.11 (1H, m), 6.57 (2H, br d , J = 8.6 Hz), 6.38 (1H, br m), 4.48 (1H, br m), 3.70 (2H, t, J = 5.2 Hz), 3.68-3.63 (10H, m), 3.55-3.53 (2H, m), 3.36 (3H, s), 3.31 (2H, m), 2.97 (3H, d, J = 4.8 Hz).
2-{[3-({4-[(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)アミノ]フェニル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物29)の製造 Example 29
2-{[3-({4-[(2,5,8,11,14-pentaoxahexadecan-16-yl) amino] phenyl} ethynyl) -1H-indazol-6-yl] thio} -N- Production of methylbenzamide (compound 29)
1H NMR (400 MHz, CDCl3) δ 11.77 (1H, br s), 7.78 (1H, br d, J = 8.4 Hz), 7.72 (1H, br s), 7.57-7.54 (1H, m), 7.41 (2H, br d, J = 8.6 Hz), 7.23-7.17 (2H, m), 7.16 (1H, dd, J = 8.4, 1.6 Hz), 7.09-7.07 (1H, m), 6.56 (2H, br d, J = 8.6 Hz), 6.46 (1H, q, J = 4.8 Hz), 4.49 (1H, br m), 3.69 (2H, t, J = 5.2 Hz), 3.66-3.60 (14H, m), 3.53-3.51 (2H, m), 3.35 (3H, s), 3.30-3.28 (2H, m), 2.96 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), N- (4-ethynylphenyl) -2,5,8,11,14- Pentaoxahexadecan-16-amine (100.0 mg, 0.28 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethylformamide (2 mL), The title compound (13.8 mg, 9%) was obtained as a brown solid in the same manner as in Example 1 using N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as a starting material.
1 H NMR (400 MHz, CDCl 3 ) δ 11.77 (1H, br s), 7.78 (1H, br d, J = 8.4 Hz), 7.72 (1H, br s), 7.57-7.54 (1H, m), 7.41 (2H, br d, J = 8.6 Hz), 7.23-7.17 (2H, m), 7.16 (1H, dd, J = 8.4, 1.6 Hz), 7.09-7.07 (1H, m), 6.56 (2H, br d , J = 8.6 Hz), 6.46 (1H, q, J = 4.8 Hz), 4.49 (1H, br m), 3.69 (2H, t, J = 5.2 Hz), 3.66-3.60 (14H, m), 3.53- 3.51 (2H, m), 3.35 (3H, s), 3.30-3.28 (2H, m), 2.96 (3H, d, J = 4.8 Hz).
2-[(3-{[5-(3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレイド)ピリジン-3-イル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物30)の製造 Example 30
2-[(3-{[5- (3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} ureido) pyridin-3-yl] ethynyl} -1H-indazol-6-yl) thio] Of N-methylbenzamide (Compound 30)
1H NMR (400 MHz, DMSO-d6) δ 13.63 (1H, br s), 8.94 (1H, br s), 8.51 (1H, d, J = 2.4 Hz), 8.39 (1H, d, J = 2.4 Hz), 8.35 (1H, br q, J = 4.4 Hz), 8.21 (1H, br d, J = 2.4 Hz), 7.86 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 7.49 (1H, dd, J = 7.4, 1.6 Hz), 7.35-7.28 (2H, m), 7.21 (1H, br d, J = 8.4 Hz), 7.07 (1H, br d, J = 7.4 Hz), 6.44 (1H, br t, J = 5.2 Hz), 3.54-3.42 (10H, m), 3.30-3.28 (2H, m), 3.24 (3H, s), 2.76 (3H, d, J = 4.4 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (5-ethynylpyridin-3-yl) -3- {2- [ 2- (2-methoxyethoxy) ethoxy] ethyl} urea (89.1 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethyl Using formamide (2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as raw materials, the title compound (40.1 mg, 28%) was obtained as a white powder in the same manner as in Example 1. .
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.63 (1H, br s), 8.94 (1H, br s), 8.51 (1H, d, J = 2.4 Hz), 8.39 (1H, d, J = 2.4 Hz), 8.35 (1H, br q, J = 4.4 Hz), 8.21 (1H, br d, J = 2.4 Hz), 7.86 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 7.49 ( 1H, dd, J = 7.4, 1.6 Hz), 7.35-7.28 (2H, m), 7.21 (1H, br d, J = 8.4 Hz), 7.07 (1H, br d, J = 7.4 Hz), 6.44 (1H , br t, J = 5.2 Hz), 3.54-3.42 (10H, m), 3.30-3.28 (2H, m), 3.24 (3H, s), 2.76 (3H, d, J = 4.4 Hz).
2-{[3-({5-[3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレイド]ピリジン-3-イル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物31)の製造 Example 31
2-{[3-({5- [3- (2,5,8,11,14-pentaoxahexadecan-16-yl) ureido] pyridin-3-yl} ethynyl) -1H-indazol-6-yl ] Production of thio} -N-methylbenzamide (Compound 31)
1H NMR (400 MHz, CD3OD) δ 8.54 (1H, br s), 8.36 (1H, br s), 8.19 (1H, t, J = 2.0 Hz), 7.90 (1H, d, J = 8.4 Hz), 7.59 (1H, s), 7.49-7.47 (1H, m), 7.37-7.30 (2H, m), 7.27-7.24 (1H, m), 7.21 (1H, dd, J = 8.4, 1.6 Hz), 3.65-3.58 (16H, m), 3.51-3.49 (2H, m), 3.41 (2H, br t, J = 5.2 Hz), 3.31 (3H, s), 2.85 (3H, s). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (5-ethynylpyridin-3-yl) -3- (2,5 , 8,11,14-Pentaoxahexadecan-16-yl) urea (114.7 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, Using the title compound (83.8 mg, 51%) as a brown solid, using N-dimethylformamide (2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as starting materials, the same procedure as in Example 1 was performed. Got as.
1 H NMR (400 MHz, CD 3 OD) δ 8.54 (1H, br s), 8.36 (1H, br s), 8.19 (1H, t, J = 2.0 Hz), 7.90 (1H, d, J = 8.4 Hz ), 7.59 (1H, s), 7.49-7.47 (1H, m), 7.37-7.30 (2H, m), 7.27-7.24 (1H, m), 7.21 (1H, dd, J = 8.4, 1.6 Hz), 3.65-3.58 (16H, m), 3.51-3.49 (2H, m), 3.41 (2H, br t, J = 5.2 Hz), 3.31 (3H, s), 2.85 (3H, s).
2-[(3-{[6-(3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレイド)ピリジン-3-イル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物32)の製造 Example 32
2-[(3-{[6- (3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} ureido) pyridin-3-yl] ethynyl} -1H-indazol-6-yl) thio] Of 2-N-methylbenzamide (Compound 32)
1H NMR (400 MHz, CDCl3) δ 11.24 (1H, br s), 8.85 (1H, br s), 8.40 (1H, d, J = 2.0 Hz), 8.16 (1H, br s), 7.75 (1H, d, J = 8.4 Hz), 7.73 (1H, dd, J = 8.4, 2.0 Hz), 7.63-7.61 (1H, m), 7.57 (1H, br s), 7.31-7.29 (2H, m), 7.24-7.22 (1H, m), 7.19 (1H, dd, J = 8.4, 1.4 Hz), 6.99 (1H, br d, J = 8.4 Hz), 6.52-6.51 (1H, br m), 3.70-3.66 (8H, m), 3.58-3.55 (4H, m), 3.37 (3H, s), 2.98 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (5-ethynylpyridin-2-yl) -3- {2- [ 2- (2-methoxyethoxy) ethoxy] ethyl} urea (82.4 mg, 0.27 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethyl Using formamide (2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as raw materials, the same operation as in Example 1 was performed to obtain the title compound (52.9 mg, 37%) as a white powder. .
1 H NMR (400 MHz, CDCl 3 ) δ 11.24 (1H, br s), 8.85 (1H, br s), 8.40 (1H, d, J = 2.0 Hz), 8.16 (1H, br s), 7.75 (1H , d, J = 8.4 Hz), 7.73 (1H, dd, J = 8.4, 2.0 Hz), 7.63-7.61 (1H, m), 7.57 (1H, br s), 7.31-7.29 (2H, m), 7.24 -7.22 (1H, m), 7.19 (1H, dd, J = 8.4, 1.4 Hz), 6.99 (1H, br d, J = 8.4 Hz), 6.52-6.51 (1H, br m), 3.70-3.66 (8H , m), 3.58-3.55 (4H, m), 3.37 (3H, s), 2.98 (3H, d, J = 4.8 Hz).
2-{[3-({6-[3-(2,5,8,11-テトラオキサトリデカン-13-イル)ウレイド]ピリジン-3-イル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物33)の製造 Example 33
2-{[3-({6- [3- (2,5,8,11-tetraoxatridecan-13-yl) ureido] pyridin-3-yl} ethynyl) -1H-indazol-6-yl] Preparation of thio} -N-methylbenzamide (compound 33)
1H NMR (400 MHz, CD3OD) δ 8.44 (1H, br d, J = 2.4 Hz), 7.84 (1H, dd, J = 8.8, 2.4 Hz), 7.76 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.48-7.46 (1H, m), 7.34-7.31 (2H, m), 7.25-7.22 (1H, m), 7.18 (1H, dd, J = 8.4, 1.6 Hz), 7.17 (1H, d, J = 8.8 Hz), 3.65-3.57 (12H, m), 3.50-3.47 (4H, m), 3.29 (3H, m), 2.85 (3H, s). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (5-ethynylpyridin-2-yl) -3- (2,5 , 8,11-Tetraoxatridecan-13-yl) urea (94.2 mg, 0.27 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N -Using the dimethylformamide (2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as starting materials, the title compound (23.3 mg, 15%) was prepared as a pale yellow solid by the same procedure as in Example 1. Got as.
1 H NMR (400 MHz, CD 3 OD) δ 8.44 (1H, br d, J = 2.4 Hz), 7.84 (1H, dd, J = 8.8, 2.4 Hz), 7.76 (1H, br d, J = 8.4 Hz ), 7.57 (1H, br s), 7.48-7.46 (1H, m), 7.34-7.31 (2H, m), 7.25-7.22 (1H, m), 7.18 (1H, dd, J = 8.4, 1.6 Hz) , 7.17 (1H, d, J = 8.8 Hz), 3.65-3.57 (12H, m), 3.50-3.47 (4H, m), 3.29 (3H, m), 2.85 (3H, s).
2-{[3-({6-[3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレイド]ピリジン-3-イル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物34)の製造 Example 34
2-{[3-({6- [3- (2,5,8,11,14-pentaoxahexadecan-16-yl) ureido] pyridin-3-yl} ethynyl) -1H-indazol-6-yl Production of thio} -N-methylbenzamide (compound 34)
1H NMR (400 MHz, CDCl3) δ 11.93 (1H, s), 8.95 (1H, br s), 8.75 (1H, s), 8.38 (1H, d, J = 2.0 Hz), 7.74 (1H, d, J = 8.0 Hz), 7.71 (1H, dd, J = 8.8, 2.0 Hz), 7.65 (1H, br s), 7.59-7.57 (1H, m), 7.26-7.23 (2H, m), 7.18-7.16 (2H, m), 7.03 (1H, d, J = 8.8 Hz), 6.54 (1H, br q, J = 4.8 Hz), 3.64-3.56 (18H, m), 3.52-3.50 (2H, m), 3.33 (3H, m), 2.98 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (5-ethynylpyridin-2-yl) -3- (2,5 , 8,11,14-Pentaoxahexadecan-16-yl) urea (106.0 mg, 0.27 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, Using N-dimethylformamide (2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as starting materials, the title compound (16.9 mg, 10%) was pale yellow by operating in the same manner as in Example 1. Obtained as a solid.
1 H NMR (400 MHz, CDCl 3 ) δ 11.93 (1H, s), 8.95 (1H, br s), 8.75 (1H, s), 8.38 (1H, d, J = 2.0 Hz), 7.74 (1H, d , J = 8.0 Hz), 7.71 (1H, dd, J = 8.8, 2.0 Hz), 7.65 (1H, br s), 7.59-7.57 (1H, m), 7.26-7.23 (2H, m), 7.18-7.16 (2H, m), 7.03 (1H, d, J = 8.8 Hz), 6.54 (1H, br q, J = 4.8 Hz), 3.64-3.56 (18H, m), 3.52-3.50 (2H, m), 3.33 (3H, m), 2.98 (3H, d, J = 4.8 Hz).
2-[(3-{[5-(3-{2-[2-(2-メトキシエトキシ)エトキシ]エチル}ウレイド)ピリジン-2-イル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物35)の製造 Example 35
2-[(3-{[5- (3- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} ureido) pyridin-2-yl] ethynyl} -1H-indazol-6-yl) thio] Of N-methylbenzamide (Compound 35)
1H NMR (400 MHz, CDCl3) δ 12.47 (1H, br s), 8.39 (1H, br s), 8.33 (1H, br s), 8.04 (1H, br dd, J = 8.4, 2.0 Hz), 7.70 (1H, br d, J = 8.4 Hz), 7.63 (1H, br s), 7.51-7.49 (1H, m), 7.38 (1H, br d, J = 8.4 Hz), 7.13-7.08 (3H, br m), 7.03-7.01 (1H, m), 6.97-6.96 (1H, br m), 6.21-6.20 (1H, br m), 3.65-3.58 (10H, m), 3.44-3.43 (2H, m), 3.36 (3H, s), 2.92 (3H, br d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (6-ethynylpyridin-3-yl) -3- {2- [ 2- (2-methoxyethoxy) ethoxy] ethyl} urea (82.4 mg, 0.27 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N-dimethyl Using formamide (2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as starting materials, the title compound (18.3 mg, 13%) was obtained as a pale yellow solid by operating in the same manner as in Example 1. It was.
1 H NMR (400 MHz, CDCl 3 ) δ 12.47 (1H, br s), 8.39 (1H, br s), 8.33 (1H, br s), 8.04 (1H, br dd, J = 8.4, 2.0 Hz), 7.70 (1H, br d, J = 8.4 Hz), 7.63 (1H, br s), 7.51-7.49 (1H, m), 7.38 (1H, br d, J = 8.4 Hz), 7.13-7.08 (3H, br m), 7.03-7.01 (1H, m), 6.97-6.96 (1H, br m), 6.21-6.20 (1H, br m), 3.65-3.58 (10H, m), 3.44-3.43 (2H, m), 3.36 (3H, s), 2.92 (3H, br d, J = 4.8 Hz).
2-{[3-({5-[3-(2,5,8,11-テトラオキサトリデカン-13-イル)ウレイド]ピリジン-2-イル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物36)の製造 Example 36
2-{[3-({5- [3- (2,5,8,11-tetraoxatridecan-13-yl) ureido] pyridin-2-yl} ethynyl) -1H-indazol-6-yl] Preparation of thio} -N-methylbenzamide (compound 36)
1H NMR (400 MHz, CD3OD) δ 8.57 (1H, br d, J = 2.4 Hz), 8.00 (1H, dd, J = 8.8, 2.4 Hz), 7.82 (1H, br d, J = 8.4 Hz), 7.60 (1H, d, J = 8.8 Hz), 7.59 (1H, br s), 7.48-7.46 (1H, m), 7.35-7.29 (2H, m), 7.24-7.22 (1H, m), 7.19 (1H, dd, J = 8.4, 1.2 Hz), 3.64-3.57 (12H, m), 3.53-3.51 (2H, m), 3.40 (2H, t, J = 5.2 Hz), 3.32 (3H, s), 2.92 (3H, s). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (6-ethynylpyridin-3-yl) -3- (2,5 , 8,11-Tetraoxatridecan-13-yl) urea (94.2 mg, 0.27 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, N -Using the dimethylformamide (2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as starting materials, the title compound (27.9 mg, 18%) was obtained as a pale yellow solid by the same procedure as in Example 1. Got as.
1 H NMR (400 MHz, CD 3 OD) δ 8.57 (1H, br d, J = 2.4 Hz), 8.00 (1H, dd, J = 8.8, 2.4 Hz), 7.82 (1H, br d, J = 8.4 Hz) ), 7.60 (1H, d, J = 8.8 Hz), 7.59 (1H, br s), 7.48-7.46 (1H, m), 7.35-7.29 (2H, m), 7.24-7.22 (1H, m), 7.19 (1H, dd, J = 8.4, 1.2 Hz), 3.64-3.57 (12H, m), 3.53-3.51 (2H, m), 3.40 (2H, t, J = 5.2 Hz), 3.32 (3H, s), 2.92 (3H, s).
2-{[3-({5-[3-(2,5,8,11,14-ペンタオキサヘキサデカン-16-イル)ウレイド]ピリジン-2-イル}エチニル)-1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物37)の製造 Example 37
2-{[3-({5- [3- (2,5,8,11,14-pentaoxahexadecan-16-yl) ureido] pyridin-2-yl} ethynyl) -1H-indazol-6-yl Production of thio} -N-methylbenzamide (Compound 37)
融点: 77-78℃
1H NMR (400 MHz, CDCl3) δ 12.00 (1H, br s), 8.50 (1H, d, J = 2.4 Hz), 8.32 (1H, s), 8.12 (1H, dd, J = 8.4, 2.4 Hz), 7.80 (1H, d, J = 8.4 Hz), 7.67 (1H, br s), 7.58-7.55 (1H, m), 7.45 (1H, d, J = 8.4 Hz), 7.22-7.19 (2H, m), 7.16 (1H, dd, J = 8.4, 1.6 Hz), 7.11-7.10 (1H, m), 6.69 (1H, br q, J = 4.8 Hz), 6.24 (1H, br m), 3.72-3.70 (4H, m), 3.68-3.64 (6H, m), 3.62-3.58 (6H, m), 3.47-3.45 (4H, m), 3.27 (3H, s), 2.96 (3H, d, J = 4.8 Hz). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- (6-ethynylpyridin-3-yl) -3- (2,5 , 8,11,14-Pentaoxahexadecan-16-yl) urea (106.0 mg, 0.27 mmol), PdCl 2 (PPh 3 ) 2 (8.4 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), N, The title compound (33.5 mg, 20%) was pale yellow using the same procedures as in Example 1 using N-dimethylformamide (2 mL) and N, N-diisopropylethylamine (0.13 mL, 0.72 mmol) as raw materials. Obtained as a solid.
Melting point: 77-78 ℃
1 H NMR (400 MHz, CDCl 3 ) δ 12.00 (1H, br s), 8.50 (1H, d, J = 2.4 Hz), 8.32 (1H, s), 8.12 (1H, dd, J = 8.4, 2.4 Hz ), 7.80 (1H, d, J = 8.4 Hz), 7.67 (1H, br s), 7.58-7.55 (1H, m), 7.45 (1H, d, J = 8.4 Hz), 7.22-7.19 (2H, m ), 7.16 (1H, dd, J = 8.4, 1.6 Hz), 7.11-7.10 (1H, m), 6.69 (1H, br q, J = 4.8 Hz), 6.24 (1H, br m), 3.72-3.70 ( 4H, m), 3.68-3.64 (6H, m), 3.62-3.58 (6H, m), 3.47-3.45 (4H, m), 3.27 (3H, s), 2.96 (3H, d, J = 4.8 Hz) .
N-{5-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]ピリジン-2-イル}-2,5,8,11-テトラオキサトリデカン-13-アミド(化合物38)の製造 Example 38
N- {5-[(6-{[2- (Methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] pyridin-2-yl} -2,5,8,11-tetraoxatri Production of decane-13-amide (compound 38)
1H NMR (400 MHz, DMSO-d6) δ 13.59 (1H, br s), 10.15 (1H, s), 8.63 (1H, dd, J = 2.4, 0.8 Hz), 8.36 (1H, q, J = 4.8 Hz), 8.18 (1H, dd, J = 8.4, 0.8 Hz), 8.10 (1H, dd, J = 8.4, 2.4 Hz), 7.87 (1H, dd, J = 8.4, 0.8 Hz), 7.61 (1H, br s), 7.50-7.48 (1H, m), 7.33 (1H, td, J = 7.6, 2.0 Hz), 7.30 (1H, td, J = 7.6, 2.0 Hz), 7.20 (1H, dd, J = 8.4, 1.2 Hz), 7.06 (1H, dd, J = 7.6, 2.0 Hz), 4.19 (2H, s), 3.70-3.68 (2H, m), 3.62-3.59 (2H, m), 3.58-3.54 (4H, m), 3.53-3.51 (2H, m), 3.43-3.41 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (120.5 mg, 0.29 mmol), N- (5-ethynylpyridin-2-yl) -2,5,8, 11-tetraoxatridecane-13-amide (162.3 mg, 0.50 mmol), PdCl 2 (PPh 3 ) 2 (6.5 mg, 0.0093 mmol), CuI (3.5 mg, 0.018 mmol), N, N-dimethylformamide (0.8 mL) and N, N-diisopropylamine (0.15 mL, 0.86 mmol) were used as starting materials, and were treated in the same manner as in Example 1 to obtain the title compound (127.0 g, 71%) as a yellow powder.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.59 (1H, br s), 10.15 (1H, s), 8.63 (1H, dd, J = 2.4, 0.8 Hz), 8.36 (1H, q, J = 4.8 Hz), 8.18 (1H, dd, J = 8.4, 0.8 Hz), 8.10 (1H, dd, J = 8.4, 2.4 Hz), 7.87 (1H, dd, J = 8.4, 0.8 Hz), 7.61 (1H, br s), 7.50-7.48 (1H, m), 7.33 (1H, td, J = 7.6, 2.0 Hz), 7.30 (1H, td, J = 7.6, 2.0 Hz), 7.20 (1H, dd, J = 8.4 , 1.2 Hz), 7.06 (1H, dd, J = 7.6, 2.0 Hz), 4.19 (2H, s), 3.70-3.68 (2H, m), 3.62-3.59 (2H, m), 3.58-3.54 (4H, m), 3.53-3.51 (2H, m), 3.43-3.41 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
N-{5-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]ピリジン-2-イル}-2,5,8,11,14-ペンタオキサヘキサデカン-16-アミド(化合物39)の製造 Example 39
N- {5-[(6-{[2- (Methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] pyridin-2-yl} -2,5,8,11,14-penta Production of oxahexadecane-16-amide (Compound 39)
1H NMR (400 MHz, DMSO-d6) δ 13.59 (1H, br s), 10.15 (1H, s), 8.64 (1H, dd, J = 2.4, 0.8 Hz), 8.36 (1H, q, J = 4.8 Hz), 8.18 (1H, dd, J = 8.4, 0.8 Hz), 8.10 (1H, dd, J = 8.4, 2.4 Hz), 7.88 (1H, br d, J = 8.4 Hz), 7.62 (1H, br s), 7.51-7.48 (1H, m), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.30 (1H, td, J = 7.6, 1.6 Hz), 7.20 (1H, dd, J = 8.4, 1.6 Hz), 7.06 (1H, dd, J = 7.6, 1.6 Hz), 4.19 (2H, s), 3.71-3.68 (2H, m), 3.62-3.60 (2H, m), 3.59-3.56 (4H, m), 3.54-3.47 (6H, m), 3.43-3.41 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (119.7 mg, 0.29 mmol), N- (5-ethynylpyridin-2-yl) -2,5,8, 11,14-pentaoxahexadecane-16-amide (140.2 mg, 0.38 mmol), PdCl 2 (PPh 3 ) 2 (5.6 mg, 0.0080 mmol), CuI (3.0 mg, 0.016 mmol), N, N-dimethylformamide ( 0.8 mL) and N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) were used as raw materials and the same operation as in Example 1 was performed to obtain the title compound (95 mg, 50%) as a white powder.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.59 (1H, br s), 10.15 (1H, s), 8.64 (1H, dd, J = 2.4, 0.8 Hz), 8.36 (1H, q, J = 4.8 Hz), 8.18 (1H, dd, J = 8.4, 0.8 Hz), 8.10 (1H, dd, J = 8.4, 2.4 Hz), 7.88 (1H, br d, J = 8.4 Hz), 7.62 (1H, br s), 7.51-7.48 (1H, m), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.30 (1H, td, J = 7.6, 1.6 Hz), 7.20 (1H, dd, J = 8.4, 1.6 Hz), 7.06 (1H, dd, J = 7.6, 1.6 Hz), 4.19 (2H, s), 3.71-3.68 (2H, m), 3.62-3.60 (2H, m), 3.59-3.56 (4H, m ), 3.54-3.47 (6H, m), 3.43-3.41 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
N-{5-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]ピリジン-2-イル}-2,5,8,11,14,17-ヘキサオキサノナデカン-19-アミド(化合物40)の製造 Example 40
N- {5-[(6-{[2- (methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] pyridin-2-yl} -2,5,8,11,14,17 Of 2-hexaoxanonadecane-19-amide (Compound 40)
1H NMR (400 MHz, DMSO-d6) δ 13.59 (1H, br s), 10.16 (1H, s), 8.64 (1H, dd, J = 2.4, 0.8 Hz), 8.37 (1H, q, J = 4.8 Hz), 8.18 (1H, dd, J = 8.8, 0.8 Hz), 8.10 (1H, dd, J = 8.8, 2.4 Hz), 7.88 (1H, br d, J = 8.4 Hz), 7.61 (1H, br s), 7.50-7.48 (1H, m), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.20 (1H, dd, J = 8.4, 1.6 Hz), 7.07-7.05 (1H, m), 4.19 (2H, s), 3.70-3.68 (2H, m), 3.62-3.60 (2H, m), 3.58-3.55 (4H, m), 3.53-3.48 (10H, m), 3.42-3.40 (2H, m), 3.22 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (108.6 mg, 0.27 mmol), N- (5-ethynylpyridin-2-yl) -2,5,8, 11,14,17-hexaoxanonadecane-19-amide (130.2 mg, 0.32 mmol), PdCl 2 (PPh 3 ) 2 (5.4 mg, 0.0077 mmol), CuI (2.7 mg, 0.014 mmol), N, N- Using dimethylformamide (0.8 mL) and N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) as raw materials, the same operation as in Example 1 was carried out to give the title compound (36.0 mg, 20%) as a light brown powder. Obtained.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.59 (1H, br s), 10.16 (1H, s), 8.64 (1H, dd, J = 2.4, 0.8 Hz), 8.37 (1H, q, J = 4.8 Hz), 8.18 (1H, dd, J = 8.8, 0.8 Hz), 8.10 (1H, dd, J = 8.8, 2.4 Hz), 7.88 (1H, br d, J = 8.4 Hz), 7.61 (1H, br s), 7.50-7.48 (1H, m), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.20 (1H, dd, J = 8.4, 1.6 Hz), 7.07-7.05 (1H, m), 4.19 (2H, s), 3.70-3.68 (2H, m), 3.62-3.60 (2H, m), 3.58-3.55 (4H, m), 3.53-3.48 (10H, m), 3.42-3.40 (2H, m), 3.22 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
N-{6-[(6-{[2-(メチルカルバモイル)フェニル]チオ}-1H-インダゾール-3-イル)エチニル]ピリジン-3-イル}-2,5,8,11-テトラオキサトリデカン-13-アミド(化合物41)の製造 Example 41
N- {6-[(6-{[2- (Methylcarbamoyl) phenyl] thio} -1H-indazol-3-yl) ethynyl] pyridin-3-yl} -2,5,8,11-tetraoxatri Production of decane-13-amide (compound 41)
1H NMR (400 MHz, DMSO-d6) δ 13.63 (1H, br s), 10.08 (1H, s), 8.80 (1H, br d, J = 2.4 Hz), 8.36 (1H, q, J = 4.8 Hz), 8.20 (1H, dd, J = 8.8, 2.4 Hz), 7.83 (1H, dd, J = 8.4, 2.4 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.62 (1H, br s), 7.50-7.48 (1H, m), 7.33 (1H, td, J = 7.6, 2.0 Hz), 7.30 (1H, td, J = 7.6, 2.0 Hz), 7.21 (1H, dd, J = 8.4, 1.2 Hz), 7.09-7.07 (1H, m), 4.16 (2H, s), 3.71-3.68 (2H, m), 3.65-3.62 (2H, m), 3.58-3.50 (6H, m), 3.43-3.41 (2H, m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (122.4 mg, 0.30 mmol), N- (6-ethynylpyridin-3-yl) -2,5,8, 11-tetraoxatridecane-13-amide (80 mg, 0.25 mmol), PdCl 2 (PPh 3 ) 2 (6.7 mg, 0.0095 mmol), CuI (3.5 mg, 0.018 mmol), N, N-dimethylformamide (0.8 mL) and N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) as raw materials and the same operation as in Example 1 gave the title compound (70.4 mg, 39%) as a light brown powder.
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.63 (1H, br s), 10.08 (1H, s), 8.80 (1H, br d, J = 2.4 Hz), 8.36 (1H, q, J = 4.8 Hz), 8.20 (1H, dd, J = 8.8, 2.4 Hz), 7.83 (1H, dd, J = 8.4, 2.4 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.62 (1H, br s) , 7.50-7.48 (1H, m), 7.33 (1H, td, J = 7.6, 2.0 Hz), 7.30 (1H, td, J = 7.6, 2.0 Hz), 7.21 (1H, dd, J = 8.4, 1.2 Hz ), 7.09-7.07 (1H, m), 4.16 (2H, s), 3.71-3.68 (2H, m), 3.65-3.62 (2H, m), 3.58-3.50 (6H, m), 3.43-3.41 (2H , m), 3.23 (3H, s), 2.76 (3H, d, J = 4.8 Hz).
2-[(3-{[4-(3-{2-[2-(2-ヒドロキシエトキシ)エトキシ]エチル}ウレイド)フェニル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物42)の製造 Example 42
2-[(3-{[4- (3- {2- [2- (2-hydroxyethoxy) ethoxy] ethyl} ureido) phenyl] ethynyl} -1H-indazol-6-yl) thio] -N-methyl Production of benzamide (compound 42)
1H NMR (400 MHz, CD3OD) δ 7.75 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.50-7.43 (5H, m), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.22 (1H, br d, J = 7.6 Hz), 7.16 (1H, dd, J = 8.4, 1.2 Hz), 3.70-3.64 (6H, m), 3.60-3.56 (4H, m), 3.39 (2H, t, J = 5.2 Hz), 2.85 (3H, s). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (119.5 mg, 0.29 mmol), 1- (4-ethynylphenyl) -3- {2- [2- (2 - hydroxyethoxy) ethoxy] ethyl} urea (93.9 mg, 0.32 mmol), PdCl 2 (PPh 3) 2 (10.5 mg, 0.015 mmol), CuI (5.5 mg, 0.029 mmol), acetonitrile (1 mL), and triethylamine ( 1 mL) was used as a starting material and the same operation as in Example 1 was performed to obtain the title compound (36.6 mg, 22%) as a pale yellow solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.75 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.50-7.43 (5H, m), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.22 (1H, br d, J = 7.6 Hz), 7.16 (1H, dd, J = 8.4, 1.2 Hz), 3.70-3.64 (6H, m), 3.60-3.56 (4H, m), 3.39 (2H, t, J = 5.2 Hz), 2.85 (3H, s).
2-[(3-{[4-(3-{2-[2-(2-アミノエトキシ)エトキシ]エチル}ウレイド)フェニル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物43)の製造 Example 43
2-[(3-{[4- (3- {2- [2- (2-Aminoethoxy) ethoxy] ethyl} ureido) phenyl] ethynyl} -1H-indazol-6-yl) thio] -N-methyl Production of benzamide (compound 43)
1H NMR (400 MHz, CD3OD) δ 7.74 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.49-7.41 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.21 (1H, br d, J = 7.6 Hz), 7.16 (1H, dd, J = 8.4, 1.2 Hz), 3.64-3.56 (6H, m), 3.51 (2H, t, J = 5.2 Hz), 3.39 (2H, t, J = 5.2 Hz), 2.85 (3H, s), 2.78 (2H, br t, J = 5.2 Hz). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (100.0 mg, 0.24 mmol), 1- {2- [2- (2-aminoethoxy) ethoxy] ethyl}- 3- (4-Ethynylphenyl) urea (84.5 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (8.6 mg, 0.012 mmol), CuI (4.6 mg, 0.024 mmol), acetonitrile (1 mL), and triethylamine ( 1 mL) was used as a starting material and the same operation as in Example 1 was performed to obtain the title compound (50.4 mg, 37%) as a pale yellow solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.74 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.49-7.41 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.21 (1H, br d, J = 7.6 Hz), 7.16 (1H, dd, J = 8.4, 1.2 Hz), 3.64-3.56 (6H, m), 3.51 (2H, t, J = 5.2 Hz), 3.39 (2H, t, J = 5.2 Hz), 2.85 (3H, s), 2.78 (2H, br t, J = 5.2 Hz).
2-{[3-({4-[3-(2-{2-[2-(ジメチルアミノ)エトキシ]エトキシ}エチル)ウレイド]フェニル}エチニル) -1H-インダゾール-6-イル]チオ}-N-メチルベンズアミド(化合物44)の製造 Example 44
2-{[3-({4- [3- (2- {2- [2- (dimethylamino) ethoxy] ethoxy} ethyl) ureido] phenyl} ethynyl) -1H-indazol-6-yl] thio}- Production of N-methylbenzamide (Compound 44)
1H NMR (400 MHz, CD3OD) δ 7.75 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.50-7.42 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.22 (1H, br d, J = 7.6 Hz), 7.17 (1H, dd, J = 8.4, 1.2 Hz), 3.62-3.55 (8H, m), 3.38 (2H, t, J = 5.6 Hz), 2.85 (3H, s), 2.53 (2H, t, J = 5.6 Hz), 2.25 (6H, s). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (119.4 mg, 0.29 mmol), 1- (2- {2- [2- (dimethylamino) ethoxy] ethoxy} ethyl) -3- (4-ethynylphenyl) urea (111.9 mg, 0.35 mmol), PdCl 2 (PPh 3) 2 (10.5 mg, 0.015 mmol), CuI (5.5 mg, 0.029 mmol), dimethylformamide (1.2 mL) , And N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) as a starting material, the same operation as in Example 1 was performed to obtain the title compound (36.4 mg, 21%) as a pale yellow solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.75 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.50-7.42 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.22 (1H, br d, J = 7.6 Hz), 7.17 (1H, dd, J = 8.4, 1.2 Hz), 3.62-3.55 (8H, m), 3.38 (2H, t, J = 5.6 Hz), 2.85 (3H, s), 2.53 (2H, t, J = 5.6 Hz), 2.25 (6H, s).
2-[(3-{[4-(3-{2-[2-(2-アセトアミドエトキシ)エトキシ]エチル}ウレイド)フェニル]エチニル}-1H-インダゾール-6-イル)チオ]-N-メチルベンズアミド(化合物45)の製造 Example 45
2-[(3-{[4- (3- {2- [2- (2-acetamidoethoxy) ethoxy] ethyl} ureido) phenyl] ethynyl} -1H-indazol-6-yl) thio] -N-methyl Production of benzamide (compound 45)
1H NMR (400 MHz, CD3OD) δ 7.76 (1H, d, J = 8.4 Hz), 7.57 (1H, s), 7.50-7.43 (5H, m), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.30 (1H, td, J = 7.6, 1.6 Hz), 7.23 (1H, br d, J = 7.6 Hz), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 3.63-3.53 (10H, m), 3.41-3.40 (2H, m), 2.85 (3H, s), 1.94 (3H, s). 2-{(3-Iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (90 mg, 0.22 mmol), N- [2- (2- {2- [3- (4-ethynylphenyl) ) Ureido] ethoxy} ethoxy) ethyl] acetamide (74 mg, 0.22 mmol), PdCl 2 (PPh 3 ) 2 (7.7 mg, 0.011 mmol), CuI (4.2 mg, 0.022 mmol), acetonitrile (1 mL), and triethylamine (1 mL) was used as a starting material and the same operation as in Example 1 was performed to obtain the title compound (31.8 mg, 24%) as a pale yellow solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.76 (1H, d, J = 8.4 Hz), 7.57 (1H, s), 7.50-7.43 (5H, m), 7.33 (1H, td, J = 7.6, 1.6 Hz), 7.30 (1H, td, J = 7.6, 1.6 Hz), 7.23 (1H, br d, J = 7.6 Hz), 7.18 (1H, dd, J = 8.4, 1.2 Hz), 3.63-3.53 (10H , m), 3.41-3.40 (2H, m), 2.85 (3H, s), 1.94 (3H, s).
N-メチル-2-[(3-{[4-(3-{2-[2-(2-モルホリノエトキシ)エトキシ]エチル}ウレイド)フェニル]エチニル}-1H-インダゾール-6-イル)チオ]ベンズアミド(化合物46)の製造 Example 46
N-methyl-2-[(3-{[4- (3- {2- [2- (2-morpholinoethoxy) ethoxy] ethyl} ureido) phenyl] ethynyl} -1H-indazol-6-yl) thio] Production of benzamide (compound 46)
1H NMR (400 MHz, CD3OD) δ 7.75 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.50-7.42 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.21 (1H, br d, J = 7.6 Hz), 7.17 (1H, dd, J = 8.4, 1.2 Hz), 3.66-3.59 (10H, m), 3.56 (2H, t, J = 5.2 Hz), 3.38 (2H, t, J = 5.2 Hz), 2.85 (3H, s), 2.55 (2H, t, J = 5.2 Hz), 2.49-2.47 (4H, m). 2-{(3-iodo-1H-indazol-6-yl) thio} -N-methylbenzamide (108.4 mg, 0.27 mmol), 1- (4-ethynylphenyl) -3- {2- [2- (2 -Morpholinoethoxy) ethoxy] ethyl} urea (105.2 mg, 0.29 mmol), PdCl 2 (PPh 3 ) 2 (9.3 mg, 0.013 mmol), CuI (5.1 mg, 0.027 mmol), dimethylformamide (1.5 mL), and N , N-diisopropylethylamine (0.14 mL, 0.80 mmol) was used as a starting material and was treated in the same manner as in Example 1 to obtain the title compound (48.1 mg, 28%) as a pale yellow solid.
1 H NMR (400 MHz, CD 3 OD) δ 7.75 (1H, br d, J = 8.4 Hz), 7.57 (1H, br s), 7.50-7.42 (5H, m), 7.32 (1H, td, J = 7.6, 1.6 Hz), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.21 (1H, br d, J = 7.6 Hz), 7.17 (1H, dd, J = 8.4, 1.2 Hz), 3.66-3.59 (10H, m), 3.56 (2H, t, J = 5.2 Hz), 3.38 (2H, t, J = 5.2 Hz), 2.85 (3H, s), 2.55 (2H, t, J = 5.2 Hz), 2.49 -2.47 (4H, m).
本発明化合物を有効成分として含有する医薬は、例えば、次のような処方によって製造することができる。 Formulation Example A pharmaceutical containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
(1)化合物1 40mg
(2)ラクトース 70mg
(3)微結晶セルロース 9mg
(4)ステアリン酸マグネシウム 1mg
1カプセル 120mg
(1)、(2)、(3)の全量、および(4)の1/2を混和した後、顆粒化する。これに残りの(4)を加えて全体をゼラチンカプセルに封入する。 1. Capsule (1) Compound 1 40mg
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) Magnesium stearate 1mg
1 capsule 120mg
The whole amount of (1), (2), (3) and 1/2 of (4) are mixed and granulated. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
(1)化合物1 40mg
(2)ラクトース 58mg
(3)コーンスターチ 18mg
(4)微結晶セルロース 3.5mg
(5)ステアリン酸マグネシウム 0.5mg
1錠 120mg
(1)、(2)、(3)の全量、(4)の2/3および(5)の1/2を混和した後、顆粒化する。残りの(4)および(5)をこの顆粒に加えて錠剤に加圧成型する。 2. Tablet (1) Compound 1 40mg
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
The whole amount of (1), (2) and (3), 2/3 of (4) and 1/2 of (5) are mixed and granulated. The remaining (4) and (5) are added to the granules and pressed into tablets.
(1)化合物1 0.1g
(2)りん酸二水素ナトリウム二水和物 0.35mg
(3)塩化ナトリウム 0.5mg
(4)塩化ベンザルコニウム 0.005g
(5)水酸化ナトリウム 適量(pH7)
(6)滅菌精製水 全量 100mL
(1)、(2)、(3)、(4)、(5)および90mLの(6)を無菌的に混和した後、適量の(6)を加えて点眼剤を調製する。 3. Eye drops (1) Compound 1 0.1 g
(2) Sodium dihydrogen phosphate dihydrate 0.35mg
(3) Sodium chloride 0.5mg
(4) Benzalkonium chloride 0.005g
(5) Sodium hydroxide appropriate amount (pH 7)
(6) Sterilized purified water, 100 mL
(1), (2), (3), (4), (5) and 90 mL of (6) are aseptically mixed, and then an appropriate amount of (6) is added to prepare an eye drop.
実施例で製造した化合物1~41を被験物質として用いた。
実施例で製造した各化合物のキナーゼ阻害活性の測定は、Off-chip Mobility Shift Assayを用いて行った。本試験のため、ヒト組換えVEGF受容体2をバキュロウイルス発現システムにて作製した。組換えタンパク質は、VEGF受容体2(NP_002244.1)の細胞質ドメイン790-1356アミノ酸を使用し、そのN末にグルタチオン-S-トランスフェラーゼ(GST)を結合することで、GST融合タンパク質として発現させた。発現させたGST-VEGF受容体2融合タンパク質は、グルタチオンセファロースクロマトグラフィーを用いて、精製を行った。また、被験物質をジメチルスルホキシドに溶解させて試験濃度の100倍濃度の溶液を調製した。さらに、その溶液をアッセイバッファー(20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH7.5)にて25倍希釈して4倍濃度被験物質溶液とした。キナーゼ阻害アッセイにおいては、CSKtideを基質として使用した。キナーゼ反応は、10 mLの2倍濃度VEGF受容体2キナーゼ溶液、アッセイバッファーにて調製した5 mLの4倍濃度被験物質溶液及び5 mLの4倍濃度基質/ATP/金属溶液をポリプロピレン製384ウェルプレートのウェル内で混合し、室温にて1時間反応させた(基質濃度:CSKtide 1000nM、ATP濃度: 75 μM、Magnesium: 5 mM)。1時間後、60 mLのTermination Buffer (QuickScout Screening Assist MSA)を添加して反応を停止させた。その後、反応溶液中の基質ペプチドとリン酸化ペプチドとをLabChip3000 system (Caliper Life Science)にて分離し、両ペプチドの定量を行った。キナーゼ反応の効率は、基質ペプチドピーク高さ(S)及びリン酸化ペプチドピーク高さ(P)から計算される生成物比(P/(P+S))にて評価した。全ての反応コンポーネントを含むコントロールウェルの平均シグナルを0% Inhibition、バックグランドウェル(酵素非添加)の平均シグナルを100% Inhibitionとし、各被験物質試験ウェルの平均シグナルから阻害率を計算した。IC50値は被験物質濃度及び阻害率から非線形最小二乗法により4パラメータのロジスティック曲線に近似させて求めた。
実施例で製造した化合物1~41のVEGF受容体2阻害活性を表1及び表2に示した。実施例で製造した化合物はVEGF受容体2のキナーゼ活性を強く阻害した。 <Test Example 1> Evaluation of Compound by VEGF Receptor 2 Kinase Inhibition Assay Compounds 1-41 produced in Examples were used as test substances.
The kinase inhibitory activity of each compound produced in the examples was measured using Off-chip Mobility Shift Assay. For this study, human recombinant VEGF receptor 2 was produced with a baculovirus expression system. The recombinant protein was expressed as a GST fusion protein by using the cytoplasmic domain 790-1356 amino acids of VEGF receptor 2 (NP_002244.1) and binding glutathione-S-transferase (GST) to its N-terminus. . The expressed GST-VEGF receptor 2 fusion protein was purified using glutathione sepharose chromatography. Further, a test substance was dissolved in dimethyl sulfoxide to prepare a solution having a concentration 100 times the test concentration. Further, the solution was diluted 25-fold with an assay buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH 7.5) to obtain a 4-fold concentration test substance solution. CSKtide was used as a substrate in the kinase inhibition assay. The kinase reaction was carried out using 10 mL of 2 × VEGF receptor 2 kinase solution, 5 mL of 4 × test substance solution prepared in assay buffer, and 5 mL of 4 × substrate / ATP / metal solution in 384-well polypropylene. The mixture was mixed in the well of the plate and reacted at room temperature for 1 hour (substrate concentration: CSKtide 1000 nM, ATP concentration: 75 μM, Magnesium: 5 mM). One hour later, 60 mL of Termination Buffer (QuickScout Screening Assist MSA) was added to stop the reaction. Thereafter, the substrate peptide and phosphorylated peptide in the reaction solution were separated by LabChip3000 system (Caliper Life Science), and both peptides were quantified. The efficiency of the kinase reaction was evaluated by the product ratio (P / (P + S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P). The average signal of control wells containing all reaction components was 0% Inhibition, the average signal of background wells (no enzyme added) was 100% Inhibition, and the inhibition rate was calculated from the average signal of each test substance test well. The IC50 value was obtained by approximating a 4-parameter logistic curve from the test substance concentration and inhibition rate using the nonlinear least square method.
Tables 1 and 2 show the VEGF receptor 2 inhibitory activities of Compounds 1-41 produced in the Examples. The compounds produced in the examples strongly inhibited the kinase activity of VEGF receptor 2.
化合物A:6-[2-(メチルカルバモイル)フェニルスルファニル]-3-E-[2-(ピリジン-2-イル)エテニル]インダゾール(一般名:アキシニチブ)
化合物B:6-[2-(メチルカルバモイル)フェニルスルファニル]-3-[2-(ピリジン-2-イル)エチニル]インダゾール
化合物Aは、Tocris Bioscience 製のアキシチニブ(カタログ番号:4350)を購入し使用した。化合物Bは、WO2006/048745の実施例20に記載の方法に従って合成した。 As a reference example, a VEGF receptor 2 kinase inhibition assay was performed in the same manner as described above using the following compound A and compound B. The results are shown in Table 2.
Compound A: 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] indazole (generic name: axinitiv)
Compound B: 6- [2- (Methylcarbamoyl) phenylsulfanyl] -3- [2- (pyridin-2-yl) ethynyl] indazole Compound A was purchased by using axitinib (catalog number: 4350) manufactured by Tocris Bioscience did. Compound B was synthesized according to the method described in Example 20 of WO2006 / 048745.
ヒト網膜微小血管内皮細胞(Cell Systems社,Human Retinal Microvascular Endothelial Cells,カタログ番号:ACBRI 181)の培養及び継代は、添付のプロトコールに準じて行った。96ウェルプレート(岩城硝子株式会社製)に接着因子溶液(Cell Systems社製,Attachment Factor)を添加し、よく馴染ませた後、除去することで、ウェルをコーティングした。続いて、血清、増殖因子及びCulture Boostを含むCS-C培地(Cell System社製,CS-C培地キット,カタログ番号:CS-4ZO-500R)に懸濁した細胞(hRMVEC)を、2×103個/100μL/ウェルの密度で播種し、37℃、5% CO2下で1日間、培養した。その後、hRMVECから培地を除去し、PBSで2回洗浄後、1%のFBS及び増殖因子を含むCS-C培地(Cell System社製,CS-C培地キット,カタログ番号:CS-4Z3-500R)で6時間、培養を行った。さらに、再度、hRMVECから培地を除去し、PBSで1回洗浄後、リコンビナント ヒトVEGF(ベクトンディッキンソン株式会社製)を含むCS-C培地(Cell System社製,CS-C培地キット,カタログ番号:CS-4ZO-500S)を用いて、各化合物を3倍公比で希釈した溶液を、1ウェル当たり100μLずつ添加し、48時間、hRMVECの培養を行った。 <Test Example 2> Growth inhibition effect of compound on proliferation of human retinal microvascular endothelial (hRMVE) cells (hRMVEC) stimulated by VEGF Human retinal microvascular endothelial cells (Cell Systems, Human Retinal Microvascular Endothelial Cells, Catalog No .: ACBRI 181 ) Was cultured and subcultured according to the attached protocol. An adhesion factor solution (Cell Systems, Attachment Factor) was added to a 96-well plate (manufactured by Iwaki Glass Co., Ltd.). Subsequently, cells (hRMVEC) suspended in CS-C medium (Cell System, CS-C medium kit, catalog number: CS-4ZO-500R) containing serum, growth factors, and Culture Boost are 2 × 10 The cells were seeded at a density of 3 cells / 100 μL / well and cultured at 37 ° C. under 5% CO 2 for 1 day. Thereafter, the medium is removed from hRMVEC, washed twice with PBS, and then CS-C medium containing 1% FBS and growth factors (Cell System, CS-C medium kit, catalog number: CS-4Z3-500R) And cultured for 6 hours. Furthermore, the medium was again removed from hRMVEC, washed once with PBS, and then CS-C medium containing recombinant human VEGF (Becton Dickinson Co., Ltd.) (Cell System, CS-C medium kit, catalog number: CS -4ZO-500S), a solution in which each compound was diluted at a common ratio of 3 was added at 100 μL per well, and hRMVEC was cultured for 48 hours.
細胞増殖阻害率(%) = 100-100×(VEGF及び化合物添加ウェルの吸光度-VEGF無添加ウェルの吸光度)/(VEGF添加ウェルの吸光度-VEGF無添加ウェルの吸光度)
また、この細胞増殖阻害率の数値を用いて、下記の計算式から50%の抑制を示す濃度であるIC50(M)を算出した。
IC50(M)=10^(LOG(A/B)×(50-C)/(D-C)+LOG(B))
A: 阻害率50%を挟む近傍の2濃度うち、高い濃度
B: 阻害率50%を挟む近傍の2濃度うち、低い濃度
C: Bでの阻害率
D: Aでの阻害率 The number of cells was measured by the MTT assay (manufactured by Dojindo Laboratories: Cell Counting Kit-8), and the growth inhibition rate of hRMVEC by the compound was calculated from the following formula.
Cell growth inhibition rate (%) = 100-100 × (absorbance in wells added with VEGF and compound-absorbance in wells without VEGF) / (absorbance in wells added with VEGF-absorbance in wells without VEGF)
Further, using this numerical value of the cell growth inhibition rate, IC50 (M), which is a concentration showing 50% inhibition, was calculated from the following calculation formula.
IC50 (M) = 10 ^ (LOG (A / B) × (50-C) / (DC) + LOG (B))
A: The higher of the two concentrations in the vicinity of the 50% inhibition rate
B: The lower of the two concentrations in the vicinity of the 50% inhibition rate
C: Inhibition rate at B
D: Inhibition rate with A
実施例で製造した化合物 1.00 mgに0.1% リン酸緩衝溶液 (pH 7.0) 1.0 mL を加えた。混合物を30秒間超音波照射した後、室温で終夜振とうした。得られた懸濁液を室温で30分間静置した後、クロマトディスク (0.20 μm) でろ過し、試料溶液とした。試料溶液及び標準溶液をLC-MS(製品名ACQUITY UPLC H-CLASS SYSTEM及びXevo TQ-S、日本ウォーターズ株式会社製)で分析し、得られたピーク面積値より外部標準法にて溶解度を算出した。
参考例として、試験例1で用いた化合物A及び化合物Bについても、同様に溶解度試験を行った。 <Test Example 3> Solubility test 1.0 mL of 0.1% phosphate buffer solution (pH 7.0) was added to 1.00 mg of the compound produced in the example. The mixture was sonicated for 30 seconds and then shaken overnight at room temperature. The obtained suspension was allowed to stand at room temperature for 30 minutes and then filtered through a chromatodisc (0.20 μm) to obtain a sample solution. The sample solution and the standard solution were analyzed by LC-MS (product names ACQUITY UPLC H-CLASS SYSTEM and Xevo TQ-S, manufactured by Nihon Waters Co., Ltd.), and the solubility was calculated by the external standard method from the obtained peak area value. .
As a reference example, the solubility test was similarly performed for Compound A and Compound B used in Test Example 1.
カラム : ACQUITY UPLC(登録商標) BEH C18, 1.7 μm, 2.1x50 mm (Waters)
移動相 : 0.006% ギ酸水溶液 : メタノール = 40 : 60 ~ 60 : 40
検出波長 : 354 nm
カラム温度 : 40℃
流速 : 0.25 mL/min
注入量 : 1.0 μL
標準溶液 : 実施例で製造した化合物 1.00 mgをメタノール (10 mL) に溶解した後、メタノールで1000倍希釈し、100 ng/mLの標準溶液を調製した。
0.1% リン酸緩衝溶液 (pH 7.0) に対する溶解度の測定結果を表4に示した。 [UPLC analysis conditions]
Column: ACQUITY UPLC® BEH C18, 1.7 μm, 2.1x50 mm (Waters)
Mobile phase: 0.006% aqueous formic acid solution: methanol = 40: 60 to 60: 40
Detection wavelength: 354 nm
Column temperature: 40 ℃
Flow rate: 0.25 mL / min
Injection volume: 1.0 μL
Standard solution: 1.00 mg of the compound produced in the example was dissolved in methanol (10 mL), and then diluted 1000 times with methanol to prepare a 100 ng / mL standard solution.
Table 4 shows the measurement results of the solubility in a 0.1% phosphate buffer solution (pH 7.0).
実施例で製造した化合物 1.00 mgをメタノール 10 mL に溶解した後、水/メタノール混合溶液 (v/v = 1:1) で希釈し、10 μg/mLの試料溶液を調製した。このサンプルを白色蛍光灯下(500 Lux)で6時間静置した後、HPLCで分析し、化合物の残存率(%)を求めた。
HPLCの分析条件は、下記のとおりである。参考例として、試験例1で用いた化合物Aについても同様の実験を行った。
残存率(光安定性)を表5に示した。実施例で製造した化合物は溶液中で光に対して安定であった。 <Test Example 4> Photostability test After dissolving 1.00 mg of the compound produced in the example in 10 mL of methanol, the sample was diluted with a water / methanol mixed solution (v / v = 1: 1) to obtain a 10 μg / mL sample. A solution was prepared. The sample was allowed to stand for 6 hours under a white fluorescent lamp (500 Lux) and then analyzed by HPLC to determine the residual ratio (%) of the compound.
The analysis conditions of HPLC are as follows. As a reference example, the same experiment was performed for Compound A used in Test Example 1.
The residual ratio (light stability) is shown in Table 5. The compounds prepared in the examples were stable to light in solution.
カラム:YMC-Pack ODS-A AA12S05-1506WT, 6.0×150mm, 5μm,(株式会社ワイエムシィ)
移動相:A液:0.01v/v%ギ酸水溶液, B液:0.01v/v%ギ酸メタノール溶液, 混合比(A:B)=4:6
検出波長:323 nm(化合物8),330 nm(化合物37),354/363 nm(化合物A Z体/E体)
カラム温度:40℃
流速:1.0 mL/min
注入量:20 μL
標準溶液: 調製直後の試料溶液を4℃に保存し、これを標準溶液として用いた。 [HPLC analysis conditions]
Column: YMC-Pack ODS-A AA12S05-1506WT, 6.0 × 150mm, 5μm, (YMC Corporation)
Mobile phase: A solution: 0.01 v / v% formic acid aqueous solution, B solution: 0.01 v / v% formic acid methanol solution, mixing ratio (A: B) = 4: 6
Detection wavelength: 323 nm (compound 8), 330 nm (compound 37), 354/363 nm (compound AZ form / E form)
Column temperature: 40 ° C
Flow rate: 1.0 mL / min
Injection volume: 20 μL
Standard solution: The sample solution immediately after preparation was stored at 4 ° C. and used as a standard solution.
実施例で製造した化合物8、27及びBについて、点眼投与後の網膜・脈絡膜組織への薬物移行濃度を測定した。本試験で使用した点眼液は、常法に従って、薬物濃度が0.25%になるように化合物8、化合物27または化合物Aをそれぞれリン酸緩衝液(pH 7.0)に懸濁させて調製された。網膜・脈絡膜組織の薬物濃度を測定するため、ウサギ(日本白色ウサギ)に1眼当たり50μLずつ点眼剤を投与し、点眼投与後2時間にウサギを安楽死させ、眼球を摘出した。摘出した眼球を液体窒素で凍結後、赤道面で2分割し、その後、後眼部側から網膜・脈絡膜組織を採取した。採取した組織から化合物を抽出するため、組織をメタノール中で細かく切断してライセートを作製した後、そのライセートを遠心分離し、上清を回収した。上清の化合抽出溶液に等量の超純水を加え、その溶液をメンブレンフィルター(0.22μm)でろ過を行い、これを最終測定溶液とした。ろ液の薬物濃度を液体クロマトグラフィー質量分析法(LC/MS/MS)で分析し、外部標準法を用いて得られたピーク面積値から網膜・脈絡膜組織中の化合物濃度を算出した。LC/MS/MSの分析条件は以下のとおりである。 <Test Example 5> Drug transferability test to retina / choroid For compounds 8, 27 and B produced in Examples, the drug transfer concentration to the retina / choroid tissue after ophthalmic administration was measured. The ophthalmic solution used in this test was prepared by suspending Compound 8, Compound 27 or Compound A in a phosphate buffer (pH 7.0) so that the drug concentration was 0.25% according to a conventional method. In order to measure the drug concentration of the retina / choroid tissue, eye drops were administered to rabbits (Japanese white rabbits) at 50 μL per eye, and the rabbits were euthanized 2 hours after the eye drops were administered, and the eyeballs were removed. The extracted eyeball was frozen with liquid nitrogen, divided into two at the equator plane, and then the retina / choroid tissue was collected from the posterior eye side. In order to extract the compound from the collected tissue, the tissue was finely cut in methanol to prepare a lysate, and then the lysate was centrifuged and the supernatant was collected. An equal amount of ultrapure water was added to the combined extraction solution of the supernatant, and the solution was filtered with a membrane filter (0.22 μm), which was used as the final measurement solution. The drug concentration of the filtrate was analyzed by liquid chromatography mass spectrometry (LC / MS / MS), and the compound concentration in the retina / choroid tissue was calculated from the peak area value obtained using the external standard method. The analysis conditions for LC / MS / MS are as follows.
装置: ACQUITY UPLC(登録商標)H-Classシステム(Waters)
カラム: ACQUITY UPLC(登録商標)BEH C18, 1.7 μm, 2.1x50 mm (Waters)
移動相: 0.006% ギ酸水溶液 : メタノール = 40 : 60 (化合物27)
0.006% ギ酸水溶液 : メタノール = 47 : 53(化合物8及びB)
検出器: ESIプローブ装備 タンデム四重極型質量分析計Xevo(登録商標) TQ-S(Waters)
イオン化モード: ESI positive ion
分析モード: MRM
Cone voltage: (化合物8)6 V,(化合物27)72 V,(化合物B)2 V
Collision energy voltage: 26 eV(化合物8); 26 eV(化合物27);18 eV(化合物B)
イオントランジッション: m/z 588.12 → 367.97(化合物8);m/z 545.18→ 393.99(化合物27);m/z 385.07 → 353.95(化合物B) [LC / MS / MS analysis conditions]
Apparatus: ACQUITY UPLC (registered trademark) H-Class system (Waters)
Column: ACQUITY UPLC® BEH C18, 1.7 μm, 2.1x50 mm (Waters)
Mobile phase: 0.006% aqueous formic acid solution: methanol = 40: 60 (compound 27)
0.006% aqueous formic acid solution: methanol = 47: 53 (compounds 8 and B)
Detector: ESI probe tandem quadrupole mass spectrometer Xevo (registered trademark) TQ-S (Waters)
Ionization mode: ESI positive ion
Analysis mode: MRM
Cone voltage: (Compound 8) 6 V, (Compound 27) 72 V, (Compound B) 2 V
Collision energy voltage: 26 eV (compound 8); 26 eV (compound 27); 18 eV (compound B)
Ion transition: m / z 588.12 → 367.97 (compound 8); m / z 545.18 → 393.99 (compound 27); m / z 385.07 → 353.95 (compound B)
The drug transfer concentrations in the retina choroid of compounds 8 and 27 were significantly higher than those of compound B (compounds B and 8: n = 6, compound 27: n = 4, p ≦ 0.05). From the results shown in Table 6, it is clear that the compound (I) of the present invention is excellent in migration to the retina / choroid tissue.
Claims (8)
- 下記一般式(I):
(式中、R1は低級アルキルを表し、X及びYは、同一又は異なって、CH又はNを表すが、但しX及びYがともにNではなく、Zは、下記一般式(a):
(式中、R2は置換基を有していてもよい低級アルキルを表し、nは1~7の整数であり、Aは、下記式:
で表される部分構造である)で表される基である)で表されるアルキニルインダゾール誘導体、又はその医薬上許容される塩。 The following general formula (I):
(Wherein R 1 represents lower alkyl, and X and Y are the same or different and represent CH or N, provided that X and Y are not both N, and Z represents the following general formula (a):
(Wherein R 2 represents optionally substituted lower alkyl, n is an integer of 1 to 7, and A is represented by the following formula:
An alkynylindazole derivative represented by the above formula, or a pharmaceutically acceptable salt thereof. - X及びYがともにCHである、請求項1に記載のアルキニルインダゾール誘導体、又はその医薬上許容される塩。 The alkynyl indazole derivative according to claim 1, wherein X and Y are both CH, or a pharmaceutically acceptable salt thereof.
- Zがパラ位に結合している、請求項1又は2に記載のアルキニルインダゾール誘導体、又はその医薬上許容される塩。 The alkynylindazole derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is bonded to the para position.
- 請求項1~4のいずれか一項に記載のアルキニルインダゾール誘導体、又はその医薬上許容される塩を含むことを特徴とする医薬。 A pharmaceutical comprising the alkynylindazole derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
- 血管内皮細胞増殖因子(VEGF)受容体チロシンキナーゼ阻害剤である、請求項5に記載の医薬。 The medicament according to claim 5, which is a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor.
- 血管新生又は浮腫を伴う網膜疾患の予防又は治療用医薬である、請求項5又は6に記載の医薬。 The medicament according to claim 5 or 6, which is a medicament for the prevention or treatment of retinal diseases associated with angiogenesis or edema.
- 血管新生又は浮腫を伴う網膜疾患が、加齢性黄斑変性症、黄斑浮腫、糖尿病性網膜症、未熟児網膜症、網膜静脈閉塞症、後発白内障、近視性脈絡膜新生血管、又は緑内障である、請求項7に記載の医薬。
The retinal disease associated with angiogenesis or edema is age-related macular degeneration, macular edema, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, secondary cataract, myopic choroidal neovascularization, or glaucoma Item 8. The medicine according to Item 7.
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